Transcription factor haploinsufficiency: when half a loaf is not enough

Two articles in this issue of the JCI (1, 2) describe haploinsufficiency of the transcription factor Nkx2-1 (also known as TTF1) as the cause of a heretofore unrecognized human syndrome characterized by neurological, thyroid, and pulmonary dysfunction.Definition of the disorder and elucidation of its cause is a real tribute to the astute clinicians who looked beyond unusual laboratory values and carefully considered the multisystem manifestations in very young patients.Affected infants had elevated levels of thyroid-stimulating hormone, and indeed some were identified by neonatal screening protocols; but this was not typical hypothyroidism, since serum thyroxine (T4) levels were normal in several infants.CNS findings were prominent but pleiotropic, including microcephaly, basal ganglia malformations, choreoathetosis, ataxia, muscular hypotonia, and developmental delays.Pulmonary problems further complicated the presentation, and symptoms ranged from neonatal, sometimes lethal respiratory distress syndromes to severe recurrent infections.While management of each individual phenotype undoubtedly consumed considerable medical attention, recognition of the composite clinical triad, CNS, thyroid, and pulmonary disease, provided the critical foothold that ultimately solved this medical mystery.Comparable multisystem deficits had been described in homozygous Nkx2-1null mice (3), which prompted genetic analyses of the human homologue NKX2.1 (also referred to as TTF1, T1TF1, and T/EBP) in these patients.Definition of mutations in NKX2.1 elucidated the molecular basis for this novel clinical triad and further indicated transcription factor haploinsufficiency as the basis for yet another human syndrome.