NKX2.1-Related Disorders: a novel mutation with mild clinical presentation
Tóm tắt
A highly variable phenotype characterized by thyroid, respiratory and neurological defects has been reported in an already established group of disorders namely NKX2.1-related disorders. We describe here the case of an infant with a novel mutation of the NKX2.1 gene characterized by mild clinical presentation. Aim of the study was to elucidate the genotype-phenotype correlation in our patient. We performed genetic analysis of the NKX2.1 gene in an infant with no neonatal respiratory distress and near-normal results at neonatal screening test for congenital hypothyroidism, choreoathetosis, ataxia and delayed independent walking. A novel mutation of the NKX2.1 gene has been identified, that is responsible for a mild framework of congenital hypothyroidism and neurological symptoms. The frequency of congenital hypothyroidism cases associated with NKX2.1 mutations is expected to be higher in a subgroup of patients, selected according to the neurological presentation. In these patients the analysis of NKX2.1 mutational status is recommended.
Tài liệu tham khảo
Montanelli L, Tonacchera M. Genetics and phenomics of hypothyroidism and thyroid dys- and agenesis due to PAX 8 and TTF1 mutations. Mol Cellul Endocrin. 2010;322:64–71.
Krude H, Schutz B, Biebermann H, Von Moers A, Schnabel D, Neitzel H, et al. Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. J Clin Invest. 2002;109:475–80.
Willemsen MA, Breedveld GJ, Wouda S, Otten BJ, Yntema JL, Lammens M, et al. Brain-Thyroid-Lung syndrome: a patient with severe multi-system disorder due to a de novo mutation in the thyroid transcription factor 1 gene. Eur J Pediatr. 2005;164:28–30.
Patel NJ, Jankovic J. NKX2-1-Related Disorders In GeneReviews®. Edited by Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K. Seattle (WA): University of Washington, Seattle. 2014; 1993–2015.
Breedveld GJ, van Dongen JWF, Danesino C, Guala A, Percy AK, Dure LS, et al. Mutations in TITF-1 are associated with benign hereditary chorea. Hum Mol Genet. 2002;11(8):971–9.
Gruters A, Krude H, Biebermann H. Molecular genetic defects in congenital hypothyroidism. Eur J Endocrinol. 2004;151:U39–44.
Asmus F, Langseth A, Doherty E, Nestor T, Munz M, Gasser T, et al. Jerky Dystonia in children: spectrum of phenotypes and genetic testing. Mov Disord. 2009;24:702–9.
Doyle DA, Gonzalez I, Thomas B, Scavina M. Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2-1. J Pediatr. 2004;145:190–3.
Maquet E, Costagliola S, Parma J, Christophe-Hobertus C, Oligny LL, Fournet JC, et al. Lethal respiratory failure and mild primary hypothyroidism in a term girl with a de novo heterozygous mutation in the TITF1/NKX2.1 gene. J Clin Endocrinol Metab. 2009;94(1):197–203.
Do Carmo Costa M, Costa C, Silva AP, Evangelista P, Santos L, Ferro A, et al. Nonsense mutation in TTF1 in a Portuguese family with benign hereditary chorea. Neurogenetics. 2005;6:209–15.
Gras D, Jonard L, Roze E, Chantot-Bastaraud S, Koht J, Motte J, et al. Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene. J Neurosurg Psychiatry. 2012;83:956–62.
Moya CM, Perez De Nanclares G, Castaño L, Potau N, Bilbao JR, Carrascosa A, et al. Functional study of a novel single deletion in the TITF1/NKX2.1 homeobox gene that produces congenital hypothyroidism and benign chorea but not pulmonary distress. J Clin Endocrinol Metab. 2006;91:1832–41.
Shetty VB, Kiraly-Borri C, Lamont P, Bikker H, Choong CSY. NKX2.1 mutations in brain-lung-thyroid syndrome: a case series of four patients. J Pediatr Endocrinol Metab 2013; doi:10.1515/jpem-2013-0109.
Guazzi S, Price M, De Felice M, Damante G, Mattei MG, Di Lauro R. Thyroid nuclear factor (TTF-1) contains a homeodomain and displays a novel DNA binding specificity. EMBO J. 1990;9:3631–9.
Kusakabe T, Kawaguchi A, Hoshi N, Kawaguchi R, Hoshi S, Kimura S. Thyroid-specific enhancer-binding protein/NKX2.1 is required for the maintenance of ordered architecture and function of the differentiated thyroid. Mol Endocrinol. 2006;20(8):1796–809.
Cao Y, Vo T, Millien G, Tagne JB, Kotton D, Mason RJ, et al. Epigenetic mechanisms modulate thyroid transcription factor 1-mediated transcription of the surfactant protein B gene. J Biol Chem. 2010;285(3):2152–64.
Guillot L, Carré A, Szinnai G, Castanet M, Tron E, Jaubert F, et al. NKX2-1 mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome”. Hum Mutat. 2010;31(2):E1146–62.
Inzelberg R, Weinberger M, Gak E. Benign hereditary chorea: An update. Parkinsonism Relat Disord. 2011;17:301–7.
Thorwarth A, Schnittert-Hubener S, Schrumpf P, Muller I, Jyrch S, Dame C, Biebermann H, Kleinau G, Katchanov J, Schulke M, Ebert G, Steininger A, Bonnemann C, Brockmann K, Christen H-J, Crock P, deZegher F, Griese M, Hewitt J, Ivarsson S, Hubner C, Kapelari K, Plecko B, Rating D, Stoeva I, Ropers H-H, Gruters A, Ullmann R, Krude H. Comprehensive genotyping and clinical characterisation reveal 27 novel Nkx2-1 mutations and expand the phenotypic spectrum J Med Genet Published Online First, April 2014. doi:10.1136/jmedgenet-2013-102248.
Barnett CP, Mencel JJ, Gecz J, Waters W, Kirwin SM, Vinette KMB, et al. Choreoathetosis, Congenital Hypothyroidism and Neonatal Respiratory Distress Syndrome With Intact NKX2-1. Am J Med Genet Part A. 2012;58A:3168–73.
Magno L, Catanzariti V, Nitsch R, Krude H, Naumann T. Ongoing expression of NKX2.1 in the postnatal mouse forebrain: potential for understanding NKX2.1 haploinsufficiency in humans? Brain Res. 2009;1304:164–86.
Peall KJ, Lumsden D, Kneen R, Madhu R, Peake D, Gibbon F, Lewis H, Hedderly T, Meyer E, Robb SA, Lynch B, King MD, Lin J-P, Morris HR, Jungbluth H, Kurian MA. Benign hereditary chorea related to NKX2.1: expansion of the genotypic and phenotypic spectrum. Dev Med Child Neurol.2013, Oct 31. doi:10.1111/dmcn.12323.
Provenzano C, Veneziano L, Appleton R, Frontali M, Civitareale D. Functional characterization of a novel mutation in TITF-1 in a patient with benign hereditary chorea. J Neurol Sciences. 2008;264:56–62.
Hamvas A, Deterding RR, Wert SE, White FV, Dishop MK, Alfano DN, et al. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest. 2013;144(3):794–804.
Ferrara AM, De Michele G, Salvatore E, Di Maio L, Zampella E, Capuano S, et al. A novel NKX2.1 mutation in a family with hypothyroidism and benign hereditary chorea. Thyroid. 2008;18(9):1005–9.
Nakamura K, Sekijima Y, Nagamatsu K, Yoshida K, Ikeda S. A novel nonsense mutation in the TITF-1 gene in a Japanese family with benign hereditary chorea. J Neurol Sci. 2012;313:189–92.
Salerno T, Peca D, Meschini L, Schivino A, Petreschi F, Occasi F, et al. Respiratory Insufficiency in a Newborn With Congenital Hypothyroidism Due To a New Mutation of TTF-1/NKX2.1 Gene. Pediatr Pulmonol. 2014;49:E42–4.