A 4-month-old female infant was admitted to the hospital for treatment of cellulitis. She also had a history of a positive newborn screen for hypothyroidism, for which she received treatment with thyroid hormone. Initial physical examination revealed a body weight below the 3rd percentile, mild tachypnea, subcostal retractions, bilateral basal lung crackles and hypoxemia. She also demonstrated mild hypotonia and gross motor delay.
Pediatric pulmonology was consulted. The patient’s initial chest radiograph and high-resolution computed tomography (HRCT) scan of the chest were normal. Nevertheless, because of the history of thyroid, brain and lung disease, an NKX2-1 gene analysis was performed. One of the two alleles showed an intronic variant that had not previously been reported. The baby was discharged home on oxygen supplementation by nasal cannula.
Over the next two years, the child suffered two episodes of respiratory failure following viral infections. By 22 months of age, the child had severe failure-to-thrive. Respiratory rate was 70/min on 2 L/min supplemental oxygen. Oxyhemoglobin saturation on room air was 82 percent. Lung exam showed severe retractions and diffuse crackles especially at the lung bases. A repeat HRCT scan showed diffuse, bilateral mixed ground-glass and ill-defined nodular opacities scattered throughout both lungs.
Treatment was begun with triple anti-inflammatory therapy consisting of prednisolone, azithromycin and hydroxychloroquine. Two months later, the child showed significant improvements in growth, respiratory rate and lung exam. By one year after initiating therapy, the child was weaned to 1 L/min supplemental oxygen, her oxyhemoglobin saturation improved to 90 percent on room air, and she did not require further hospitalization.
Respirations were 42/min and comfortable. Lung exam showed no retractions and only sparse crackles at the bases. The prednisolone was progressively weaned to every other day therapy. Ophthalmology examination was normal and there was no hematologic, hepatic or renal toxicity.
Review of the family history revealed three additional family members with thyroid, brain or lung disease. A younger sister was born with congenital hypothyroidism, and during the first year of life she developed two pneumonias requiring hospitalization and oxygen therapy. Mother also had a history of neonatal lung disease, gait ataxia and tremors, and maternal aunt had hypothyroidism. Genetic testing of these three individuals demonstrated the same NKX2-1 variant as the older sister, substantiating the pathogenic nature of this genetic variant.
The NKX2-1 gene encodes thyroid transcription factor 1, a transcription factor required for the expression of surfactant proteins A, B, and C, as well as ABCA3, a lipid transporter involved in pulmonary surfactant biogenesis. Mutations in NKX2-1 have been linked to the development of pulmonary disease (neonatal respiratory distress syndrome or children’s interstitial lung disease), thyroid dysfunction (hypothyroidism), and neurologic abnormalities (typically benign hereditary chorea).
The University of Michigan C.S. Mott Children’s Hospital is one of a small number of centers participating in the Children’s Interstitial Lung Disease (ChILD) research network.
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Originally posted January 2016