ESPE Abstracts

Introduction: Brain-lung-thyroid syndrome (BLTS) is a rare autosomal dominant or de novo condition that occurs in early childhood, associated with mutations of the NKX2-1 (Thyroid transcription factor 1) gene present in chromosome 14q13. This protein plays a critical role during organogenesis of basal ganglia, lungs, including surfactant production and homeostasis, and thyroid. The clinical spectrum varies from the complete triad of brain-lung-thyroid syndrome (50%) to brain and thyroid disease (30%), or isolated Benign Hereditary Chorea (13%). Pulmonary manifestations can include respiratory distress syndrome in neonates, interstitial lung disease in young children and pulmonary fibrosis in older individuals. There is an increased risk of pulmonary carcinoma in young adults. Thyroid dysfunction can present as congenital or compensated hypothyroidism.

Case Reviews: Patient 1 is a male, 4-month-old, born at 40+4 weeks gestation by normal vaginal delivery, weighing 3.070 Kg and head circumference 34.5 cm. There were no complications antenatally, postnatally he had transient tachypnoea of the newborn self-resolved by 3 hours of age. However, there was family history of NKX2-1 mutation in father (BHC) and 2 older brothers (5-year-old oxygen dependant, chest problems, global developmental delay and no thyroid problems and a 3-year-old with chorea and congenital hypothyroidism). Infant was noted to have congenital hypothyroidism on Newborn Screening. Thyroid function was compensated when tested after neonatal screening (TSH 11 mU/l, free T4 of 20 pmol/L). Patient 2 is a female, 7-year-old, born at 41 weeks gestation by normal vaginal delivery, weighing 3.420 Kg and head circumference 35 cm. She had an uneventful postnatal period, but her Newborn Screening showed Congenital Hypothyroidism (TSH 31 mU/l, free T4 of 10.2 pmol/L). She was started on Levothyroxine, currently on 40 micrograms once a day. By 5 months of age, she had feeding problems, central hypotonia, recurrent chest infections, peculiar face and laryngomalacia. She was referred to Genetics, NKX2-1 and PAX-9 mutations confirmed. At the age of 7 years, the child has severe global developmental delay, hypotonia, oligodontia but no movement disorders.

Discussion: Prognosis varies considerably depending on the severity of symptoms. BHC causes life-long morbidity of varying degrees. Lung disease is associated with high mortality. Disease phenotype and severity varies even within families with the same NKX2-1 mutation. The absence of a classical triad doesn’t exclude BLTS, therefore presence of congenital hypothyroidism in association with respiratory or neurological findings should prompt early diagnosis of affected patients and counselling of their families.