ESPE Abstracts

Background: Genetic defects in NKX2.1 (chromosome 14q13) are associated with hypothyroidism, choreo-athetotic movements and respiratory distress, known as the “Brain-Lung-Thyroid syndrome”.

Objective and hypotheses: To identify the genetic basis of a disorder compatible with the “NKX2.1 syndrome” and extra features outside the typical triad.

Patients and methods: 10-year old girl with congenital hypothyroidism on levo-thyroxine replacement, generalized hypotonia, mild respiratory distress at birth and following subsequent episodes of bronchiolitis. At follow-up delay on achievement of motor milestones, including late-onset walking, clumsiness, frequent falls and language delay. In early infancy she presented subtle choreic movements in extremities. Also, delayed teeth eruption (17 months) and partial absence of permanent teeth at age 10 in orthopantomography. Finally, marked joint hyper-extensibility of the upper arms was evidenced. Brain MRI, electromyogram and thyroid ultrasound were normal. Her parents and brother were healthy. PCR-Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA) and SNP array were performed.

Results: With suspicion of NKX2.1 syndrome, the whole coding region of NKX2.1 was PCR-amplified and directly sequenced, rendering normal results. Considering the strong consistency of diagnosis, MLPA was performed showing heterozygous loss of gen dosage in 3 probes corresponding to the gene. The defect was de novo and absent in the parental study. To identify the precise deletion size of this copy number variation (CNV) a Genomic SNP Array was performed showing a deletion of 3.44 Mb (14q13.2-q21.1) including NKX2.1 and 30 additional genes.

Conclusion: A novel de novo deletion was identified as cause of the NKX2.1 syndrome. When clinical suspicion is fully consistent, monoallelic deletions of 14q should be searched for in these patients through genomic techniques that detect gene-dosage variations. Haploinsufficiency of PAX9 is responsible for hypodontia, and we propose the presence of a still unidentified candidate gene for joint hyper-extensibility within the deleted genetic interval.