- Email: [email protected]
Pediatric Interstitial Lung Disease
(Dr Lavoie), Hôpital du Sacré-Coeur de Montréal; Department of Psychology (Dr Lavoie), Université du Québec à Montréal; and Research Centre (Dr Lavoie), Montréal Heart Institute. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: Abebaw M. Yohannes, PhD, FCCP, Department of Health Professions, Research Institute for Health and Social Care, Manchester Metropolitan University, Elizabeth Gaskell Campus, Hathersage Rd, M13 0JA, Manchester, England; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0511
References 1. Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, Ustun B. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet. 2007;370(9590): 851-858. 2. Maurer J, Rebbapragada V, Borson S, et al; ACCP Workshop Panel on Anxiety and Depression in COPD. Anxiety and depression in COPD: current understanding, unanswered questions, and research needs. Chest. 2008;134(suppl 4): 43S-56S. 3. Yohannes AM, Willgoss TG, Baldwin RC, Connolly MJ. Depression and anxiety in chronic heart failure and chronic obstructive pulmonary disease: prevalence, relevance, clinical implications and management principles. Int J Geriatr Psychiatry. 2010;25(12):1209-1221. 4. DiMatteo MR, Lepper HS, Croghan TW. Depression is a risk factor for noncompliance with medical treatment: metaanalysis of the effects of anxiety and depression on patient adherence. Arch Intern Med. 2000;160(14):2101-2107. 5. Khdour MR, Hawwa AF, Kidney JC, Smyth BM, McElnay JC. Potential risk factors for medication non-adherence in patients with chronic obstructive pulmonary disease (COPD). Eur J Clin Pharmacol. 2012;68(10):1365-1373. 6. Moser DK, McKinley S, Riegel B, et al. Relationship of persistent symptoms of anxiety to morbidity and mortality outcomes in patients with coronary heart disease. Psychosom Med. 2011;73(9):803-809. 7. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet. 1997;349(9064):1498-1504. 8. Wittchen HU, Jacobi F, Rehm J, et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol. 2011;21(9):655-679. 9. Pająk A, Jankowski P, Kotseva K, Heidrich J, de Smedt D, De Bacquer D; EUROASPIRE Study Group. Depression, anxiety, and risk factor control in patients after hospitalization for coronary heart disease: the EUROASPIRE III Study. Eur J Prev Cardiol. 2013;20(2):331-340. 10. Atlantis E, Fahey P, Cochrane B, Smith S. Bidirectional associations between clinically relevant depression or anxiety and COPD: a systematic review and meta-analysis. Chest. 2013; 144(3):766-777. 11. Ng TP, Niti M, Tan WC, Cao Z, Ong KC, Eng P. Depressive symptoms and chronic obstructive pulmonary disease: effect on mortality, hospital readmission, symptom burden, functional status, and quality of life. Arch Intern Med. 2007;167(1): 60-67. 12. Laurin C, Moullec G, Bacon SL, Lavoie KL. Impact of anxiety and depression on chronic obstructive pulmonary disease exacerbation risk. Am J Respir Crit Care Med. 2012;185(9): 918-923.
Pediatric Interstitial Lung Disease Thyroid Transcription Factor-1 Mutations and Their Phenotype Potpourri interstitial and diffuse lung disease (ChILD) Childhood is a compilation of rare pediatric diseases affecting
lung parenchyma and airways, varying in severity and outcome. A subgroup of ChILD includes diseases of surfactant dysfunction, which typically present in the newborn period as neonatal respiratory distress syndrome and are associated with congenital alveolar proteinosis. Genetic causes of errors in surfactant metabolism include mutations in surfactant protein (SP)-B, SP-C, and an ATP-binding cassette protein (ABCA3). Thyroid transcription factor (TTF)-1 mutations, too, have been implicated in cases of surfactant dysfunction, although classically in the form of brain-thyroid-lung disease, in which the affected patient also has neurologic impairment and thyroid dysfunction. However, in this issue of CHEST (see page 794), Hamvas et al1 specifically describe the pulmonary phenotype associated with TTF-1 mutations, which may or may not include neurologic or thyroid abnormalities. TTF (TTF-1, TITF1) is a homeobox transcription factor also known as NK2 homeobox 1 (NKX2.1) or thyroid enhancer binding protein (TEBP) and has long been recognized for its involvement in lung, thyroid, and forebrain embryogenesis. TTF-1 knockout mice lack thyroid glands, lungs, pituitary gland, and ventral forebrain, whereas mice that are heterozygous for the knockout gene remain predominantly asymptomatic2; however, heterozygous humans show an array of diseases. A TTF-1 mutation was first described in humans in 1998, when a term infant who developed respiratory failure shortly after delivery and neonatal subclinical hypothyroidism exhibited developmental delays and recurrent lower airway infection and atelectasis. Karyotype analysis revealed a deletion of chromosome 14q13-20 with corresponding absence of the TTF-1 gene.3 Since this discovery, numerous other cases related to haploinsufficiency of TTF-1 have been reported as part of brain-thyroid-lung disease. Hamvas et al1 look specifically at the array of pulmonary phenotypes associated with TTF-1 mutations by identifying cases suspected of ChILD and testing for TTF-1. Although the majority of affected individuals had brain and/or thyroid involvement, five individuals exclusively had lung involvement, three of whom were related. Moreover, the cohort of patients with TTF-1 mutations did not exclusively have congenital alveolar proteinosis but had a range of pulmonary
728
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Editorials
manifestations. This array of findings is explained by the complex role that TTF-1 plays in pulmonary physiology, affecting not just surfactant function but also embryonic morphogenesis and innate immune responses. As in SP-B, SP-C, and ABCA3 mutations, TTF-1 mutations have been shown to cause surfactant dysfunction. TTF-1 is expressed in type 2 pneumocytes and directly regulates transcription of surfactant proteins.4 The end result is congenital alveolar proteinosis with resultant respiratory distress syndrome and interstitial lung disease, as was frequently seen in the cohort. Furthermore, TTF-1 plays a critical role in lung embryogenesis. The lung bud develops from an endodermal outpouching off the foregut that separates from the primitive esophagus by formation of a septum. Lack of TTF-1 results in failure to create a septum in murine models and ultimately resembles severe cases of cleft larynx with an esophago-tracheal fistula.5 Indeed, one of the cases in this series exhibited a laryngeal cleft and associated hypothyroidism. TTF-1 is also essential for embryonic lung epithelial development, lung branching morphogenesis, and alveolarization.6 A range of pulmonary hypoplasia anomalies was identified, including extensive enlargement of alveolar spaces; this range is expected in view of the role of TTF-1 in a multitude of pulmonary developmental processes. A common feature of these cases was frequent respiratory tract infections. In two patients with severe respiratory syncytial viral (RSV) infections, there was reduced SP-D expression. However, this reduction of expression may be secondary to the viral infection itself, as TTF-1 in murine models only regulates SP-D expression indirectly and is unlikely to have a significant role in the control of SP-D expression.7 TTF-1 does regulate expression of a number of proteins involved in the lung innate defenses, including SP-A and club cell secretory protein (Clara).8,9 However, in this cohort, SP-A expression was not altered. The role of club cell secretory protein was not explored but could have important implications for infections such as RSV and the interstitial lung phenotype. The club cell secretory protein, which is involved in antiinflammatory and immunomodulatory pathways, damps the immune response to infections like RSV and other injuries like ozone.10 An overactive immune system could play a role in the development of interstitial lung disease. None of the patients in this case series developed lung cancer, yet TTF-1 has been documented as a marker for pulmonary adenocarcinoma.11 Indeed, Willemsen et al12 have described a case of large cell lung cancer occurring in a 23-year-old patient with brain-thyroid-lung syndrome, which raises the concerning possibility of increased lung cancer risk in these patients. Lung cancer screening and management are questions that have yet to be addressed.
As in previously reported cases, all patients were heterozygous for their mutations or deletions of the TTF-1 gene. Most of the mutations were localized to exon 2 and exon 3 of chromosome 14. These authors were able to observe clinical propensities related to mutation size and location and postulated that epigenetic effects may also affect phenotypic variability and outcomes given the degree of phosphorylation and epigenetic modification homeobox proteins undergo. Although this is not the first case series outlining the clinical manifestations of TTF-1 mutations, this is the first series, to our knowledge, to describe the breadth of pulmonary presentations and outcomes associated with a TTF-1 mutation, ranging from surfactant dysfunction, developmental dysregulation, and diminished innate defenses. Although TTF-1 mutations are often thought of in the context of brain-thyroidlung syndrome, it is clear that pulmonary disease may be the primary manifestation of this disease. Lael M. Yonker, MD T. Bernard Kinane, MD Boston, MA Affiliations: From the Division of Pediatric Pulmonology, Department of Pediatrics, Massachusetts General Hospital. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: T. Bernard Kinane, MD, Division of Pediatric Pulmonology, Department of Pediatrics, Massachusetts General Hospital, 175 Cambridge St, 5th Floor, Boston, MA 02114; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0550
References 1. Hamvas A, Deterding RR, Wert SE, et al. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest. 2013;144(3): 794-804. 2. Kimura S, Hara Y, Pineau T, et al. The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev. 1996;10(1):60-69. 3. Devriendt K, Vanhole C, Matthijs G, de Zegher F. Deletion of thyroid transcription factor-1 gene in an infant with neonatal thyroid dysfunction and respiratory failure. N Engl J Med. 1998;338(18):1317-1318. 4. Ikeda K, Clark JC, Shaw-White JR, Stahlman MT, Boutell CJ, Whitsett JA. Gene structure and expression of human thyroid transcription factor-1 in respiratory epithelial cells. J Biol Chem. 1995;270(14):8108-8114. 5. Minoo P, Su G, Drum H, Bringas P, Kimura S. Defects in tracheoesophageal and lung morphogenesis in Nkx2.1(-/-) mouse embryos. Dev Biol. 1999;209(1):60-71. 6. Minoo P, Hamdan H, Bu D, Warburton D, Stepanik P, deLemos R. TTF-1 regulates lung epithelial morphogenesis. Dev Biol. 1995;172(2):694-698. 7. Kolla V, Gonzales LW, Gonzales J, et al. Thyroid transcription factor in differentiating type II cells: regulation, isoforms,
journal.publications.chestnet.org
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and target genes. Am J Respir Cell Mol Biol. 2007;36(2): 213-225. 8. Bruno MD, Bohinski RJ, Huelsman KM, Whitsett JA, Korfhagen TR. Lung cell-specific expression of the murine surfactant protein A (SP-A) gene is mediated by interactions between the SP-A promoter and thyroid transcription factor-1. J Biol Chem. 1995;270(12):6531-6536. 9. Zhang L, Whitsett JA, Stripp BR. Regulation of Clara cell secretory protein gene transcription by thyroid transcription factor-1. Biochim Biophys Acta. 1997;1350(3):359-367.
10. Wang H, Liu Y, Liu Z. Clara cell 10-kD protein in inflammatory upper airway diseases. Curr Opin Allergy Clin Immunol. 2013;13(1):25-30. 11. Yatabe Y, Mitsudomi T, Takahashi T. TTF-1 expression in pulmonary adenocarcinomas. Am J Surg Pathol. 2002;26(6): 767-773. 12. Willemsen MA, Breedveld GJ, Wouda S, et al. Brain-ThyroidLung syndrome: a patient with a severe multi-system disorder due to a de novo mutation in the thyroid transcription factor 1 gene. Eur J Pediatr. 2005;164(1):28-30.
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Editorials
References 1. Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, Ustun B. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet. 2007;370(9590): 851-858. 2. Maurer J, Rebbapragada V, Borson S, et al; ACCP Workshop Panel on Anxiety and Depression in COPD. Anxiety and depression in COPD: current understanding, unanswered questions, and research needs. Chest. 2008;134(suppl 4): 43S-56S. 3. Yohannes AM, Willgoss TG, Baldwin RC, Connolly MJ. Depression and anxiety in chronic heart failure and chronic obstructive pulmonary disease: prevalence, relevance, clinical implications and management principles. Int J Geriatr Psychiatry. 2010;25(12):1209-1221. 4. DiMatteo MR, Lepper HS, Croghan TW. Depression is a risk factor for noncompliance with medical treatment: metaanalysis of the effects of anxiety and depression on patient adherence. Arch Intern Med. 2000;160(14):2101-2107. 5. Khdour MR, Hawwa AF, Kidney JC, Smyth BM, McElnay JC. Potential risk factors for medication non-adherence in patients with chronic obstructive pulmonary disease (COPD). Eur J Clin Pharmacol. 2012;68(10):1365-1373. 6. Moser DK, McKinley S, Riegel B, et al. Relationship of persistent symptoms of anxiety to morbidity and mortality outcomes in patients with coronary heart disease. Psychosom Med. 2011;73(9):803-809. 7. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet. 1997;349(9064):1498-1504. 8. Wittchen HU, Jacobi F, Rehm J, et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol. 2011;21(9):655-679. 9. Pająk A, Jankowski P, Kotseva K, Heidrich J, de Smedt D, De Bacquer D; EUROASPIRE Study Group. Depression, anxiety, and risk factor control in patients after hospitalization for coronary heart disease: the EUROASPIRE III Study. Eur J Prev Cardiol. 2013;20(2):331-340. 10. Atlantis E, Fahey P, Cochrane B, Smith S. Bidirectional associations between clinically relevant depression or anxiety and COPD: a systematic review and meta-analysis. Chest. 2013; 144(3):766-777. 11. Ng TP, Niti M, Tan WC, Cao Z, Ong KC, Eng P. Depressive symptoms and chronic obstructive pulmonary disease: effect on mortality, hospital readmission, symptom burden, functional status, and quality of life. Arch Intern Med. 2007;167(1): 60-67. 12. Laurin C, Moullec G, Bacon SL, Lavoie KL. Impact of anxiety and depression on chronic obstructive pulmonary disease exacerbation risk. Am J Respir Crit Care Med. 2012;185(9): 918-923.
Pediatric Interstitial Lung Disease Thyroid Transcription Factor-1 Mutations and Their Phenotype Potpourri interstitial and diffuse lung disease (ChILD) Childhood is a compilation of rare pediatric diseases affecting
lung parenchyma and airways, varying in severity and outcome. A subgroup of ChILD includes diseases of surfactant dysfunction, which typically present in the newborn period as neonatal respiratory distress syndrome and are associated with congenital alveolar proteinosis. Genetic causes of errors in surfactant metabolism include mutations in surfactant protein (SP)-B, SP-C, and an ATP-binding cassette protein (ABCA3). Thyroid transcription factor (TTF)-1 mutations, too, have been implicated in cases of surfactant dysfunction, although classically in the form of brain-thyroid-lung disease, in which the affected patient also has neurologic impairment and thyroid dysfunction. However, in this issue of CHEST (see page 794), Hamvas et al1 specifically describe the pulmonary phenotype associated with TTF-1 mutations, which may or may not include neurologic or thyroid abnormalities. TTF (TTF-1, TITF1) is a homeobox transcription factor also known as NK2 homeobox 1 (NKX2.1) or thyroid enhancer binding protein (TEBP) and has long been recognized for its involvement in lung, thyroid, and forebrain embryogenesis. TTF-1 knockout mice lack thyroid glands, lungs, pituitary gland, and ventral forebrain, whereas mice that are heterozygous for the knockout gene remain predominantly asymptomatic2; however, heterozygous humans show an array of diseases. A TTF-1 mutation was first described in humans in 1998, when a term infant who developed respiratory failure shortly after delivery and neonatal subclinical hypothyroidism exhibited developmental delays and recurrent lower airway infection and atelectasis. Karyotype analysis revealed a deletion of chromosome 14q13-20 with corresponding absence of the TTF-1 gene.3 Since this discovery, numerous other cases related to haploinsufficiency of TTF-1 have been reported as part of brain-thyroid-lung disease. Hamvas et al1 look specifically at the array of pulmonary phenotypes associated with TTF-1 mutations by identifying cases suspected of ChILD and testing for TTF-1. Although the majority of affected individuals had brain and/or thyroid involvement, five individuals exclusively had lung involvement, three of whom were related. Moreover, the cohort of patients with TTF-1 mutations did not exclusively have congenital alveolar proteinosis but had a range of pulmonary
728
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 09/03/2013
Editorials
manifestations. This array of findings is explained by the complex role that TTF-1 plays in pulmonary physiology, affecting not just surfactant function but also embryonic morphogenesis and innate immune responses. As in SP-B, SP-C, and ABCA3 mutations, TTF-1 mutations have been shown to cause surfactant dysfunction. TTF-1 is expressed in type 2 pneumocytes and directly regulates transcription of surfactant proteins.4 The end result is congenital alveolar proteinosis with resultant respiratory distress syndrome and interstitial lung disease, as was frequently seen in the cohort. Furthermore, TTF-1 plays a critical role in lung embryogenesis. The lung bud develops from an endodermal outpouching off the foregut that separates from the primitive esophagus by formation of a septum. Lack of TTF-1 results in failure to create a septum in murine models and ultimately resembles severe cases of cleft larynx with an esophago-tracheal fistula.5 Indeed, one of the cases in this series exhibited a laryngeal cleft and associated hypothyroidism. TTF-1 is also essential for embryonic lung epithelial development, lung branching morphogenesis, and alveolarization.6 A range of pulmonary hypoplasia anomalies was identified, including extensive enlargement of alveolar spaces; this range is expected in view of the role of TTF-1 in a multitude of pulmonary developmental processes. A common feature of these cases was frequent respiratory tract infections. In two patients with severe respiratory syncytial viral (RSV) infections, there was reduced SP-D expression. However, this reduction of expression may be secondary to the viral infection itself, as TTF-1 in murine models only regulates SP-D expression indirectly and is unlikely to have a significant role in the control of SP-D expression.7 TTF-1 does regulate expression of a number of proteins involved in the lung innate defenses, including SP-A and club cell secretory protein (Clara).8,9 However, in this cohort, SP-A expression was not altered. The role of club cell secretory protein was not explored but could have important implications for infections such as RSV and the interstitial lung phenotype. The club cell secretory protein, which is involved in antiinflammatory and immunomodulatory pathways, damps the immune response to infections like RSV and other injuries like ozone.10 An overactive immune system could play a role in the development of interstitial lung disease. None of the patients in this case series developed lung cancer, yet TTF-1 has been documented as a marker for pulmonary adenocarcinoma.11 Indeed, Willemsen et al12 have described a case of large cell lung cancer occurring in a 23-year-old patient with brain-thyroid-lung syndrome, which raises the concerning possibility of increased lung cancer risk in these patients. Lung cancer screening and management are questions that have yet to be addressed.
As in previously reported cases, all patients were heterozygous for their mutations or deletions of the TTF-1 gene. Most of the mutations were localized to exon 2 and exon 3 of chromosome 14. These authors were able to observe clinical propensities related to mutation size and location and postulated that epigenetic effects may also affect phenotypic variability and outcomes given the degree of phosphorylation and epigenetic modification homeobox proteins undergo. Although this is not the first case series outlining the clinical manifestations of TTF-1 mutations, this is the first series, to our knowledge, to describe the breadth of pulmonary presentations and outcomes associated with a TTF-1 mutation, ranging from surfactant dysfunction, developmental dysregulation, and diminished innate defenses. Although TTF-1 mutations are often thought of in the context of brain-thyroidlung syndrome, it is clear that pulmonary disease may be the primary manifestation of this disease. Lael M. Yonker, MD T. Bernard Kinane, MD Boston, MA Affiliations: From the Division of Pediatric Pulmonology, Department of Pediatrics, Massachusetts General Hospital. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: T. Bernard Kinane, MD, Division of Pediatric Pulmonology, Department of Pediatrics, Massachusetts General Hospital, 175 Cambridge St, 5th Floor, Boston, MA 02114; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0550
References 1. Hamvas A, Deterding RR, Wert SE, et al. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest. 2013;144(3): 794-804. 2. Kimura S, Hara Y, Pineau T, et al. The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev. 1996;10(1):60-69. 3. Devriendt K, Vanhole C, Matthijs G, de Zegher F. Deletion of thyroid transcription factor-1 gene in an infant with neonatal thyroid dysfunction and respiratory failure. N Engl J Med. 1998;338(18):1317-1318. 4. Ikeda K, Clark JC, Shaw-White JR, Stahlman MT, Boutell CJ, Whitsett JA. Gene structure and expression of human thyroid transcription factor-1 in respiratory epithelial cells. J Biol Chem. 1995;270(14):8108-8114. 5. Minoo P, Su G, Drum H, Bringas P, Kimura S. Defects in tracheoesophageal and lung morphogenesis in Nkx2.1(-/-) mouse embryos. Dev Biol. 1999;209(1):60-71. 6. Minoo P, Hamdan H, Bu D, Warburton D, Stepanik P, deLemos R. TTF-1 regulates lung epithelial morphogenesis. Dev Biol. 1995;172(2):694-698. 7. Kolla V, Gonzales LW, Gonzales J, et al. Thyroid transcription factor in differentiating type II cells: regulation, isoforms,
journal.publications.chestnet.org
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 09/03/2013
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and target genes. Am J Respir Cell Mol Biol. 2007;36(2): 213-225. 8. Bruno MD, Bohinski RJ, Huelsman KM, Whitsett JA, Korfhagen TR. Lung cell-specific expression of the murine surfactant protein A (SP-A) gene is mediated by interactions between the SP-A promoter and thyroid transcription factor-1. J Biol Chem. 1995;270(12):6531-6536. 9. Zhang L, Whitsett JA, Stripp BR. Regulation of Clara cell secretory protein gene transcription by thyroid transcription factor-1. Biochim Biophys Acta. 1997;1350(3):359-367.
10. Wang H, Liu Y, Liu Z. Clara cell 10-kD protein in inflammatory upper airway diseases. Curr Opin Allergy Clin Immunol. 2013;13(1):25-30. 11. Yatabe Y, Mitsudomi T, Takahashi T. TTF-1 expression in pulmonary adenocarcinomas. Am J Surg Pathol. 2002;26(6): 767-773. 12. Willemsen MA, Breedveld GJ, Wouda S, et al. Brain-ThyroidLung syndrome: a patient with a severe multi-system disorder due to a de novo mutation in the thyroid transcription factor 1 gene. Eur J Pediatr. 2005;164(1):28-30.
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Editorials