NKX2-1 mutations in brain-lung-thyroid syndrome: a case series of four patients

Abstract

Brain-lung-thyroid syndrome (BLTS) characterized by congenital hypothyroidism, respiratory distress syndrome, and benign hereditary chorea is caused by thyroid transcription factor 1 (NKX2-1/TTF1) mutations. We report the clinical and molecular characteristics of four cases presenting with primary hypothyroidism, respiratory distress, and neurological disorder. Two of the four patients presenting with the triad of BLTS had NKX2-1 mutations, and one of these NKX2-1 [c.890_896del (p.Ala327Glyfs*52)] is a novel variant. The third patient without any identified NKX2-1 mutations was a carrier of mitochondrial mutation; this raises the possibility of mitochondrial mutations contributing to thyroid dysgenesis. Although rare, the triad of congenital hypothyroidism, neurological, and respiratory signs is highly suggestive of NKX2-1 anomalies. Screening for NKX2-1 mutations in patients with thyroid, lung, and neurological abnormalities will enable a unifying diagnosis and genetic counseling for the affected families. In addition, identification of an NKX2-1 defect would be helpful in allaying the concerns about inadequate thyroxine supplementation as the cause of neurological defects observed in some children with congenital hypothyroidism.

Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer

“…A mutation in NKX2-1 , known as thyroid transcription factor ( TTF) 1 , is a causative mutation for brain–lung–thyroid syndrome characterized by congenital hypothyroidism, respiratory distress syndrome and benign hereditary chorea27. In a previous GWAS for DTC, one common variant (rs944289), located near MBIP/NKX2-1 , was associated with the mentioned diseases810 and several studies validated the association1516.…”

Spatiotemporal transcriptomic atlas of mouse organogenesis using DNA nanoball-patterned arrays

“…As informative examples, NKX2-1, which is mutated in brainlung-thyroid syndrome (Shetty et al, 2014), was mainly enriched in brain (hippocampus and subpallium) and lung and Lmod3, which is associated with nemaline myopathy (Berkenstadt et al, 2018), was enriched in the skeletal muscle (Figure 6B).…”

Prenatal Diagnosis and Management of a Fetal Goiter Hypothyroidism due to Dyshormonogenesis

“…However, it has not been well established with hypothyroidism, except for NKX2-1-related disorder. This is also known as brain-lung-thyroid syndrome and manifests with childhood-onset chorea, CH, and neonatal respiratory distress [9]. The initial respiratory distress showed in the immediately neonatal period of our case was interpreted as resulting from a complication of goiter itself linked to upper airway obstruction.…”