Brain-Lung-Thyroid Syndrome

Brain-lung-thyroid syndrome is a rare disorder characterized by congenital hypothyroidism (CH), infant respiratory distress syndrome (IRDS) and benign hereditary chorea (BHC; see these terms).

Epidemiology

Prevalence is unknown but to date about 50 cases have been reported in the literature.

Clinical description

The clinical spectrum varies from the complete triad of brain-lung-thyroid syndrome (50%), to brain and thyroid disease (30%), or isolated BHC (13%), which is the mildest expression of the syndrome. In addition, the severity of symptoms varies widely, even in families with the same disease-causing mutation. The thyroid form can present with overt or, more commonly, subclinical hypothyroidism / hyper-thyrotropinemia at birth, in infancy or in early childhood. There is significant correlation between thyroid morphology (55% normal, 35% hemiagenesis or hypoplasia, and 10% athyreosis in 46 published cases) and the commonly mild elevation of thyroid-stimulating hormone (TSH). The lung form presents most commonly as IRDS at term, suggestive for congenital surfactant protein deficiency. In a subgroup of patients, the disease progresses to chronic interstitial lung disease. In other patients, recurrent mild to severe pulmonary infections may be the initial sign of lung disease. The neurological form presents during the first year of life with hypotonia and psychomotor delay, which progresses to BHC between 1 and 5 years of age. Non-progressive BHC after the age of 5 years is the most common and specific sign of the syndrome. Additional non-classical symptoms including hypo- or oligodontia, microcephaly, intellectual deficit, failure to thrive, growth retardation, dysmorphism, hypoparathyroidism and malabsorption have been reported only in patients with large deletions on chromosome 14 including the NKX2-1 gene. Mild intellectual deficit may be present in some patients.

Etiology

Brain-lung-thyroid syndrome is caused by mutations in the thyroid transcription factor 1 gene (NKX2-1/TITF1; 14q13.3).

Diagnostic methods

Diagnosis is based on neonatal screening rather than clinical presentation of overt hypothyroidism such as feeding difficulty, prolonged jaundice, or large fontanels. Congenital hypothyroidism is screened systematically in many countries and raises suspicion of NKX2-1 defects when found in combination with neurological or respiratory problems. Diagnosis of BHC is based on clinical observation. Cerebral MRI may reveal malformations in about 20% of patients (e.g. dysgenetic basal ganglia, or cerebral atrophy). Diagnosis of brain-lung-thyroid syndrome is confirmed by genetic testing showing mutations in the NKX2-1 gene.

Differential diagnosis

Differential diagnoses include other forms of congenital hypothyroidism, other causes of infant respiratory distress syndrome, genetic forms of surfactant protein deficiency, and other causes of chorea.

Genetic counseling

Genetic counseling of families is essential in the context of autosomal dominant transmission due to life-long morbidity.

Management and treatment

Treatment of congenital hypothyroidism is based on life-long levothyroxin substitution according to international guidelines (starting dose 10-15 mcg/kg/day). Treatment of compensated hypothyroidism / hyperthyrotropinemia should be considered as early as possible. Patients with IRDS at term may require mechanical ventilation for up to several weeks. Treatment options for BHC are not well established.

Prognosis

Prognosis varies considerably depending on the severity of symptoms. BHC causes life-long morbidity of varying degrees. Lung disease, if present, can cause mortality in a subgroup of patients.