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NKX2-1-Related Disorders.


Patel NJ1, Jankovic J2.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
2014 Feb 20 [updated 2016 Jul 29].

Author information

Assistant Professor, Movement Disorders Center, Henry Ford Health System, Neuroscience Institute, Department of Neurology, West Bloomfield, Michigan
Professor of Neurology, Distinguished Chair in Movement Disorders, Director, Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Department of Neurology, Houston, Texas



NKX2-1-related disorders range from benign hereditary chorea (BHC) to choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress (also known as brain-lung-thyroid syndrome). Childhood-onset chorea, the hallmark of NKX2-1-related disorders, may or may not be associated with respiratory distress syndrome or congenital hypothyroidism. Chorea generally begins in early infancy or about age one year (most commonly) or in late childhood or adolescence, and progresses 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 persons. The risk for pulmonary carcinoma is increased in young adults with an NKX2-1-related disorder. Thyroid dysfunction, the result of dysembryogenesis, can present as congenital hypothyroidism or compensated hypothyroidism. The risk for thyroid cancer is unknown and may not be increased. In one review, 50% of affected individuals had the full brain-lung-thyroid syndrome, 30% had involvement of brain and thyroid only, and 13% had isolated chorea only.


The diagnosis of an NKX2-1-related disorder is established in a proband by identification of a heterozygous pathogenic variant in NKX2-1.


Treatment of manifestations: Tetrabenazine in low doses reduces chorea. Levodopa has been reported to improve chorea in four children with substantial improvement in gait symptoms (falls); it 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 in the usual manner for asthma and interstitial lung disease; hypothyroidism is treated with thyroid replacement therapy. Surveillance: For individuals with no or minimal neurologic manifestations: Annual neurologic evaluation. For individuals with no or minimal pulmonary manifestations, starting at the time of diagnosis: Annual pulmonary function tests and chest x-ray or CT scan of the chest to screen for pulmonary malignancy. For individuals with no or minimal manifestations of thyroid disease, starting at the time of diagnosis: Annual serum thyroid-stimulating hormone and physical examination (including thyroid palpation) to screen for thyroid cancer. Evaluation of relatives at risk: In a family in which the NKX2-1 pathogenic variant has been identified, testing of at-risk relatives prenatally or as soon as possible after birth allows early identification of infants at high risk for congenital hypothyroidism and pulmonary disease to permit early diagnosis and management, particularly to prevent the neurodevelopmental consequences of untreated hypothyroidism. In a family with benign hereditary chorea or brain-lung-thyroid syndrome in which a pathogenic variant has not been identified, assessing thyroid function of at-risk infants as soon as possible after birth allows early identification and management of congenital hypothyroidism. Pregnancy management: Prior to pregnancy or early in gestation, it is recommended that a woman work with her physician to determine the safety for the fetus of the use of any medication she is taking for chorea.


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 pregnancies at increased risk is a possible option.

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