Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency

Abstract

The occurrence of neurological symptoms and developmental delay in patients affected by congenital hypothyroidism (CH) has been attributed to the lack of thyroid hormone in the developing CNS. Accordingly, after the introduction of neonatal screening programs for CH, which allowed early and adequate treatment, an almost normal outcome for most CH patients could be achieved. However, a few patients did not reach this favorable outcome despite early and adequate treatment. Here we describe five patients with variable degrees of CH who suffered from choreoathetosis, muscular hypotonia, and pulmonary problems, an association of symptoms that had not been described before this study. Since this clinical picture matched the phenotype of mice targeted for deletion of the transcription factor gene Nkx2-1, we investigated the human NKX2-1 gene in these five patients. We found heterozygous loss of function mutations in each of these five patients, e.g., one complete gene deletion, one missense mutation (G2626T), and three nonsense mutations (2595insGG, C2519A, C1302A). Therefore, the unfavorable outcome in patients with CH, especially those with choreoathetosis and pulmonary symptoms, can be explained by mutations in the NKX2-1 gene rather than by hypothyroidism. Moreover, the association of symptoms in the patients with NKX2-1 mutations points to an important role of human NKX2-1 in the development and function of thyroid, basal ganglia, and lung, as already described for rodents.

Novel GLIS3 mutations demonstrate an extended multisystem phenotype

“…PAX8 and thyroid transcription factor1 (TTF1/NK2 homeobox-1:NKX2-1) are involved in thyroid cell differentiation and proliferation and subsequent expression of genes encoding for thyroglobulin, thyroid peroxidase, thyrotropin receptor (TSHR) genes and the sodium-iodide symporter (7)(8)(9)(10). Mutations in PAX8 and NKX2-1 result in significant phenotypic variability, with patients presenting with hypothyrodisim, normal serum T 4 with hyperthyrotropinaemia (compensated hypothyroidism) and euthyroidism due to variable gene penetrance and expression, with a thyroid size ranging from normal to severe hypoplasia and athyreosis (11)(12)(13)(14)(15)(16). However, despite these phenotypic similarities there is no evidence for conserved GLI transcriptionbinding sites in the PAX8, NKX2-1 or TSHR flanking gene sequences.…”

European Society for Paediatric Endocrinology Consensus Guidelines on Screening, Diagnosis, and Management of Congenital Hypothyroidism

“…The identification of a NKX2-1 mutation implies that special attention should be paid to neurological development and to lung disease in the follow-up of affected children [139,140]. The identification of a FOXE1 mutation implies that special attention should be paid to neurological development [141].…”

NovelNKX2-1Frameshift Mutations in Patients with Atypical Phenotypes of the Brain-Lung-Thyroid Syndrome

“…In humans, heterozygous loss-of-function mutations in NKX2-1 gene (OMIM #600635) have been reported to cause a complex phenotype called brain-lung-thyroid (BLT) syndrome (OMIM #610978) [1,2,3,4,5,6,7]. The BLT syndrome is a rare disease characterized by a highly variable penetrance and expressivity and combining neurological manifestations (hypotonia evolving into benign chorea and ataxia), pulmonary disease (neonatal respiratory distress and/or interstitial lung disease), and congenital hypothyroidism (CH) of variable severity, associated either with athyreosis, hypoplasia or an apparently normal gland in situ [1,2,3,4,5,6,7], but not with ectopy as recently indicated also in the document of the CH Consensus Conference Group [8].…”

“…The BLT syndrome is a rare disease characterized by a highly variable penetrance and expressivity and combining neurological manifestations (hypotonia evolving into benign chorea and ataxia), pulmonary disease (neonatal respiratory distress and/or interstitial lung disease), and congenital hypothyroidism (CH) of variable severity, associated either with athyreosis, hypoplasia or an apparently normal gland in situ [1,2,3,4,5,6,7], but not with ectopy as recently indicated also in the document of the CH Consensus Conference Group [8]. NKX2-1 variants had also been reported in isolated benign hereditary chorea (BHC; OMIM #118700) [9].…”