ESPE Abstracts

Background: Brain-lung-thyroid syndrome (BLTS, OMIM# 610978) is caused by mutations in the NK2 homeobox 2 (NKX2-1; TTF1) gene affecting the three NKX2-1 expressing organs brain, lung and thyroid. The syndrome is characterized by benign hereditary chorea (BHC), infant respiratory distress syndrome (IRDS) and congenital hypothyroidism (CH). However, the clinical spectrum and severity of symptoms vary widely. Regarding the increasing number of published mutations and heterogeneous phenotypes a clinical synopsis is needed for all involved specialists.

Objectives: Summarising all available published cases of NKX2-1 related disorders to provide a detailed clinical overview of BLTS.

Methods: We performed a systematic review of literature in MEDLINE and EMBASE. All subjects with proven NKX2-1 mutations and description of symptoms were included. For genotype-phenotype association studies, we compared different functional domains of the protein with specific phenotypes by Pearson’s chi-square test.

Results: We identified 243 subjects with 137 different mutations. Brain was affected in 91% of cases, lung in 56% and thyroid in 68%. Patients with brain involvement showed choreoathetosis (87%), developmental delay (61%) and muscular hypotonia (36%). Patients with lung disease showed IRDS (38%), recurrent lower respiratory tract infection (57%) and chronic interstitial lung disease (25%). Only 60% of patients with CH were detected by neonatal screening (mean TSH 130 mU/l), while 40% were diagnosed later (mean TSH 29 mU/l). In 202 subjects, information on all three organs was available for phenotype analysis: Only 44% suffered from the complete triad of BLTS, brain-thyroid-phenotype occurred in 29 and 15% showed isolated brain involvement. Further a detailed genotype-phenotype analysis revealed significant correlations between specific phenotypes and affected gene domains.

Conclusion: We provide a detailed clinical and genetic overview of BLTS with new insights in the heterogeneous symptoms and genotype-phenotype correlation of the syndrome.