Penetrance

No studies have evaluated the penetrance of NKX2-1 pathogenic variants to date. Published case series provide limited descriptions of penetrance across families, though intrafamilial variation has been reported.

Source: GeneReviews — "NKX2-1-Related Disorders"

Diagnostic Criteria

Suggestive Findings

NKX2-1-related disorders should be suspected in probands with the following clinical and laboratory findings and family history.

Clinical findings

• Infancy- or childhood-onset non-progressive chorea that may or may not be associated with:

• Mild neurologic symptoms including axial hypotonia, ataxia, developmental delays, impaired mobility of upper and lower limbs;

• Congenital hypothyroidism;

• Respiratory distress syndrome;

OR

• A history of congenital hypothyroidism and:

• Neurologic manifestations including hypotonia, neurodevelopmental delay, seizures; and/or

• Respiratory dysfunction including interstitial lung disease in children.

Laboratory findings

Source: GeneReviews — "NKX2-1-Related Disorders"

Differential Diagnosis

The differential diagnosis of NKX2-1-related disorders includes hereditary and acquired causes of chorea, congenital hypothyroidism, and respiratory insufficiency. Table 3a. Selected Hereditary Disorders in the Differential Diagnosis of NKX2-1-Related Disorders

Management Guidelines

No clinical practice guidelines for NKX2-1-related disorders have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with an NKX2-1-related disorder, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. NKX2-1-Related Disorders: Recommended Evaluations Following Initial Diagnosis

Source: GeneReviews — "NKX2-1-Related Disorders"

Clinical Guidance

Although reported amelioration of choreic movements in an individual with benign hereditary chorea treated with olanzapine for psychosis, dopamine receptor blockers are not recommended as a first-line therapy for the treatment of chorea. Olanzapine and dopamine receptor blockers, while effective in treating choreiform movements, are associated with a small risk of developing tardive dyskinesia, which can worsen choreiform movements long term. Due to the risk of pulmonary disease in NKX2-1-related disorders, exposure to smoking may exacerbate pulmonary dysfunction and increase the risk of lung cancer in affected individuals.

Source: GeneReviews — "NKX2-1-Related Disorders"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "NKX2-1-Related Disorders"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended.

Table 6.

NKX2-1-Related Disorders: Recommended Surveillance

System/Concern | Evaluation | Frequency

Neurologic (esp chorea)

| Neurologic eval | Annually or more frequently as needed (incl persons w/o neurologic manifestations)

Pulmonary

| • Pulmonary eval

• Pulmonary function tests

• Lung imaging (chest x-ray or chest CT scan) to screen for pulmonary malignancy

| Annually or more frequently as needed (incl persons w/o pulmonary manifestations)

Thyroid

| • Eval w/endocrinologist

• Thyroid function tests (T4, TSH)

• Physical exam incl palpation of thyroid to assess for thyroid cancer

| Annually or more frequently as needed (incl persons w/o endocrine manifestations)

T4 = thyroxine; TSH = thyroid-stimulating hormone

Source: GeneReviews — "NKX2-1-Related Disorders"