Choreoathetosis, congenital hypothyroidism and neonatal respiratory distress syndrome with intact NKX2‐1

Mutations in the NK2 homeobox 1 gene (NKX2-1) cause a rare syndrome known as choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome (OMIM 610978). Here we present the first reported patient with this condition caused by a 14q13.3 deletion which is adjacent to but does not interrupt NKX2-1, and review the literature on this condition. The infant presented at 23 months with a history of developmental delay, hyperkinesia, recurrent respiratory infections, neonatal respiratory distress, and hypothyroidism. Choreiform movements and delayed motor milestones were first noted at 6–8 months of age. TSH levels had been consistently elevated from 8 months of age. The clinical presentation was suggestive of an NKX2-1 mutation. Sequencing of all exons and splice site junctions of NKX2-1 was performed but was normal. Array CGH was then performed and a 3.29 Mb interstitial deletion at 14q13.1–q13.3 was detected. The distal region of loss of the deletion disrupted the surfactant associated 3 (SFTA3) gene but did disrupt NKX2-1. Findings were confirmed on high resolution SNP array and multiplex semiquanitative PCR. NKX2-1 encodes transcriptional factors involved in the developmental pathways for thyroid, lung, and brain. We hypothesize that the region centromeric to NKX2-1 is important for the normal functioning of this gene and when interrupted produces a phenotype that is typical of the choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome, as seen in our patient. We conclude that deletions at 14q13.3 adjacent to but not involving NKX2-1 can cause choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome. © 2012 Wiley Periodicals, Inc.