Correspondence
Deletion of Thyroid Transcription Factor-1 Gene in an Infant with Neonatal Thyroid Dysfunction and Respiratory Failure
N Engl J Med 1998; 338:1317-1318April 30, 1998
- Article
To the Editor:
The thyroid and lungs develop as outgrowths of the ventral foregut. Differentiation and early function of both organs appear to be related through the common expression of the thyroid transcription factor-1 (TTF-1) gene on chromosome 14q13. In embryos, the pattern of expression of this gene is largely restricted to the epithelium of the developing thyroid and airways and the ventral forebrain.1 Experimental evidence suggests that TTF-1 mediates thyroid-specific gene transcription and pulmonary production of surfactant proteins.2,3 We identified a heterozygous deletion of the TTF-1 gene in a newborn infant with thyroid dysfunction and respiratory failure.
The infant was referred 15 hours after birth at term (weight, 3.4 kg; length, 48 cm; head circumference, 36 cm) because of severe respiratory distress and required ventilation therapy for one week. On admission, her serum thyrotropin concentration was high (60 mU per liter) and the serum thyroxine concentration was normal (8.9 μg per deciliter [114 nmol per liter]). On day 19, the serum thyrotropin concentration was still high (48 mU per liter) and the serum thyroxine concentration was normal (13.9 μg per deciliter [179 nmol per liter]). Technetium scanning revealed a normal-sized thyroid gland, but the uptake of technetium was low. Therapy with thyroxine was initiated. At the age of three months, withdrawal of thyroxine was followed by a rise in the serum thyrotropin concentration to 24 mU per liter within one month, and thyroxine therapy was resumed. The course during infancy was complicated by lower-airway infections with atelectasis of the right upper lobe. The morphology of the bronchial tree was normal, as judged by bronchoscopy. At the age of 2 years, mental and motor development were delayed by 4 and 12 months, respectively, and there was hypotonia and truncal ataxia. Magnetic resonance imaging of the brain revealed no abnormalities.
High-resolution G-banding showed a deletion of chromosome 14q13–21 that had arisen spontaneously. Fine mapping with a panel of polymorphic microsatellite markers identified a deleted region of less than 13 cM on the paternal chromosome, flanked by markers D14S1049 and D14S984, showing a biparental pattern of inheritance. For markers D14S75, D14S288, and D14S1014, only the maternal allele was inherited. Fluorescence in situ hybridization with cosmid probes from TTF-1 (gift of Dr. J.A. Whitsett, Cincinnati) and PAX9 genes (gift of Dr. M. Busslinger, Vienna, Austria) yielded signals only on maternal chromosome 14 (Figure 1Figure 1
Genetic Studies in an Infant with Neonatal Thyroid Dysfunction and Respiratory Failure.).This child presented with a unique combination of unexplained neonatal respiratory failure and a high serum thyrotropin concentration without overt hypothyroidism. TTF-1 has been proposed to have a dual role in both the morphogenesis and function of the thyroid and lung.1-3 Accordingly, TTF-1 haploinsufficiency is compatible with the occurrence of thyroid dyshormonogenesis and with reduced surfactant production and neonatal respiratory distress. Outside the thyroid gland and lungs, the expression of the TTF-1 gene appears to be confined to the diencephalic structures within the developing brain.1 Haploinsufficiency for the TTF-1 gene may have contributed to the developmental delay in this child, but other genes in the deleted region may be involved. There was also a heterozygous deletion of the PAX9 gene; this gene is thought to participate in the morphogenesis of the vertebral column, limbs, and pharyngeal-pouch derivatives.4 No clinical correlate was apparent in the infant.
4 ReferencesKoenraad Devriendt, M.D., Ph.D.
Christine Vanhole, M.D.
Gert Matthijs, Ph.D.
Francis de Zegher, M.D., Ph.D.
University of Leuven, 3000 Leuven, Belgium1
Lazzaro D ,Price M ,de Felice M ,Di Lauro R . The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain. Development 1991;113:1093-1104
Web of Science | Medline2
Civitareale D ,Castelli MP ,Falasca P ,Saiardi A . Thyroid transcription factor 1 activates the promoter of the thyrotropin receptor gene. Mol Endocrinol 1993;7:1589-1595
CrossRef | Web of Science | Medline3
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;270:8108-8114
CrossRef | Web of Science | Medline4
Neubuser A ,Koseki H ,Balling R . Characterization and developmental expression of Pax9, a paired-box-containing gene related to Pax1. Dev Biol 1995;170:701-716
CrossRef | Web of Science | Medline
- Citing Articles (52)
Citing Articles
1
Katsuya Nakamura, Yoshiki Sekijima, Kiyoshiro Nagamatsu, Kunihiro Yoshida, Shu-ichi Ikeda. (2012) A novel nonsense mutation in the TITF-1 gene in a Japanese family with benign hereditary chorea. Journal of the Neurological Sciences 313:1-2, 189-192
CrossRef2
R. Epaud, L. Jonard, H. Ducou-le-Pointe, C. Delestrain, P. Fanen, L. Guillot, F. Flamein. (2012) Pathologies génétiques du surfactant. Archives de Pédiatrie
CrossRef3
Edina Torgyekes, Alan L. Shanske, Kwame Anyane-Yeboa, Odelia Nahum, Sara Pirzadeh, Einat Blumfield, Vaidehi Jobanputra, Dorothy Warburton, Brynn Levy. (2011) The proximal chromosome 14q microdeletion syndrome: Delineation of the phenotype using high resolution SNP oligonucleotide microarray analysis (SOMA) and review of the literature. American Journal of Medical Genetics Part A 155:8, 1884-1896
CrossRef4
Rivka Inzelberg, Moran Weinberger, Eva Gak. (2011) Benign hereditary chorea: An update. Parkinsonism & Related Disorders 17:5, 301-307
CrossRef5
Galit Kleiner-Fisman. 2011. Benign hereditary chorea. , 199-212.
CrossRef6
Lawrence M. Nogee. (2010) Genetic Basis of Children's Interstitial Lung Disease. Pediatric Allergy, Immunology, and Pulmonology 23:1, 15-24
CrossRef7
Lawrence M. Nogee. (2010) Genetic Basis of Children’s Interstitial Lung Disease. Pediatric Allergy, Immunology, and Pulmonology110525163459060
CrossRef8
Harvey S. Singer, Jonathan W. Mink, Donald L. Gilbert, Joseph Jankovic. 2010. Chorea, Athetosis, and Ballism. , 76-96.
CrossRef9
Joachim Pohlenz, Guy Van Vliet. 2010. Developmental Abnormalities of the Thyroid. , 97-104.
CrossRef10
Janine F. Felix, Elisabeth M. de Jong, Claudine P. Torfs, A. de Klein, Robbert J. Rottier, Dick Tibboel. (2009) Genetic and environmental factors in the etiology of esophageal atresia and/or tracheoesophageal fistula: An overview of the current concepts. Birth Defects Research Part A: Clinical and Molecular Teratology 85:9, 747-754
CrossRef11
A. Carre, G. Szinnai, M. Castanet, S. Sura-Trueba, E. Tron, I. Broutin-L'Hermite, P. Barat, C. Goizet, D. Lacombe, M.-L. Moutard, C. Raybaud, C. Raynaud-Ravni, S. Romana, H. Ythier, J. Leger, M. Polak. (2009) Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case. Human Molecular Genetics 18:12, 2266-2276
CrossRef12
E. S. W. Ngan, B. H. H. Lang, T. Liu, C. K. Y. Shum, M.-T. So, D. K. C. Lau, T. Y. Y. Leon, S. S. Cherny, S. Y. Tsai, C.-Y. Lo, U.-S. Khoo, P. K. H. Tam, M.-M. Garcia-Barcelo. (2009) A Germline Mutation (A339V) in Thyroid Transcription Factor-1 (TITF-1/NKX2.1) in Patients With Multinodular Goiter and Papillary Thyroid Carcinoma. JNCI Journal of the National Cancer Institute 101:3, 162-175
CrossRef13
Alfonso Massimiliano Ferrara, Giuseppe De Michele, Elena Salvatore, Luigi Di Maio, Emilia Zampella, Serena Capuano, Giuseppina Del Prete, Giuseppina Rossi, Gianfranco Fenzi, Alessandro Filla, Paolo Emidio Macchia. (2008) A Novel NKX2.1 Mutation in a Family with Hypothyroidism and Benign Hereditary Chorea. Thyroid 18:9, 1005-1009
CrossRef14
Sebastián A. Esperante, Carina M. Rivolta, Lucrecia Miravalle, Viviana Herzovich, Sonia Iorcansky, Marco Baralle, Héctor M. Targovnik. (2008) Identification and characterization of four PAX8 rare sequence variants (p.T225M, p.L233L, p.G336S and p.A439A) in patients with congenital hypothyroidism and dysgenetic thyroid glands. Clinical Endocrinology 68:5, 828-835
CrossRef15
Claudia Provenzano, Liana Veneziano, Richard Appleton, Marina Frontali, Donato Civitareale. (2008) Functional characterization of a novel mutation in TITF-1 in a patient with benign hereditary chorea. Journal of the Neurological Sciences 264:1-2, 56-62
CrossRef16
Keisuke NAGASAKI, Satoshi NARUMI, Tadashi ASAMI, Toru KIKUCHI, Tomonobu HASEGAWA, Makoto UCHIYAMA. (2008) Mutation of a Gene for Thyroid Transcription Factor-1 (TITF1) in a Patient with Clinical Features of Resistance to Thyrotropin. Endocrine Journal 55:5, 875-878
CrossRef17
Zhe Feng YUAN, Hua Qing MAO, Yan Fei LUO, Yi Dong WU, Zheng SHEN, Zheng Yan ZHAO. (2008) Thyrotropin Receptor and Thyroid Transcription Factor-1 Genes Variant in Chinese Children with Congenital Hypothyroidism. Endocrine Journal 55:2, 415-423
CrossRef18
Galit Kleiner-Fisman, Anthony E. Lang. (2007) Benign hereditary chorea revisited: A journey to understanding. Movement Disorders 22:16, 2297-2305
CrossRef19
Aurore Carré, Mireille Castanet, Sylvia Sura-Trueba, Gabor Szinnai, Guy Vliet, Delphine Trochet, Jeanne Amiel, Juliane Léger, Paul Czernichow, Virginie Scotet, Michel Polak. (2007) Polymorphic length of FOXE1 alanine stretch: evidence for genetic susceptibility to thyroid dysgenesis. Human Genetics 122:5, 467-476
CrossRef20
Jun Kimura, Gail H. Deutsch. (2007) Key Mechanisms of Early Lung Development. Pediatric and Developmental Pathology 10:5, 335-347
CrossRef21
Esad Koklu, Tamer Gunes, Mehmet Adnan Ozturk, Mustafa Akcakus, Derya Buyukkayhan, Selim Kurtoglu. (2007) Cutis Laxa Associated with Central Hypothyroidism owing to Isolated Thyrotropin Deficiency in a Newborn. Pediatric Dermatology 24:5, 525-528
CrossRef22
David Devos, Isabelle Vuillaume, Alix De Becdelievre, Berengère De Martinville, Claire-Marie Dhaenens, Jean-Christophe Cuvellier, Jean-Marie Cuisset, Louis Vallée, Marie-Pierre Lemaitre, Hélène Bourteel, Eric Hachulla, Benoit Wallaert, Alain Destée, Luc Defebvre, Bernard Sablonnière. (2006) New syndromic form of benign hereditary chorea is associated with a deletion of TITF-1 and PAX-9 contiguous genes. Movement Disorders 21:12, 2237-2240
CrossRef23
Anissa Djemli, Guy Van Vliet, Edgard E. Delvin. (2006) Congenital hypothyroidism: From paracelsus to molecular diagnosis. Clinical Biochemistry 39:5, 511-518
CrossRef24
John S Fuqua. (2006) Genetics, clinical management and natural history of congenital hypothyroidism. Expert Review of Endocrinology & Metabolism 1:2, 265-279
CrossRef25
Marian Ludgate, Dagmar Fuhrer. 2006. Thyroid Dysfunction: Molecular Genetics. .
CrossRef26
Maria Carmo Costa, Cristina Costa, Ana Paula Silva, Pedro Evangelista, Luís Santos, Anabela Ferro, Jorge Sequeiros, Patrícia Maciel. (2005) Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea. Neurogenetics 6:4, 209-215
CrossRef27
Deepak Kamnasaran, Chih-Ping Chen, Koenraad Devriendt, Lakshmi Mehta, Diane W. Cox. (2005) Defining a holoprosencephaly locus on human chromosome 14q13 and characterization of potential candidate genes. Genomics 85:5, 608-621
CrossRef28
Michel A. A. P. Willemsen, Guido J. Breedveld, Siep Wouda, Barto J. Otten, Jan L. Yntema, Martin Lammens, Bert B. A. Vries. (2005) Brain-Thyroid-Lung syndrome: a patient with a severe multi-system disorder due to a de novo mutation in the thyroid transcription factor 1 gene. European Journal of Pediatrics 164:1, 28-30
CrossRef29
Marina Baldini, Alessandra Orsatti, Luigi Cantalamessa. (2005) A Singular Case of Graves’ Disease in Congenital Thyroid Hemiagenesis. Hormone Research 63:3, 107-110
CrossRef30
Frederick Groenman, Sharon Unger, Martin Post. (2005) The Molecular Basis for Abnormal Human Lung Development. Biology of the Neonate 87:3, 164-177
CrossRef31
J. F. Felix, R. Keijzer, M. F. Dooren, R. J. Rottier, D. Tibboel. (2004) Genetics and developmental biology of oesophageal atresia and tracheo-oesophageal fistula: lessons from mice relevant for paediatric surgeons. Pediatric Surgery International 20:10, 731-736
CrossRef32
Akira Hishinuma, Narumi Ohmika, Takashi Namatame, Tamio Ieiri. (2004) TTF-2 stimulates expression of 17 genes, including one novel thyroid-specific gene which might be involved in thyroid development. Molecular and Cellular Endocrinology 221:1-2, 33-46
CrossRef33
Meyer Knobel, Geraldo Medeiros-Neto. (2003) An Outline of Inherited Disorders of the Thyroid Hormone Generating System. Thyroid 13:8, 771-801
CrossRef34
Dominique Meunier, Jos
e Aubin, Lucie Jeannotte. (2003) Perturbed thyroid morphology and transient hypothyroidism symptoms inHoxa5 mutant mice. Developmental Dynamics 227:3, 367-378
CrossRef35
Ordan J Lehmann, Jane C Sowden, Peter Carlsson, Tim Jordan, Shomi S Bhattacharya. (2003) Fox's in development and disease. Trends in Genetics 19:6, 339-344
CrossRef36
Moreno, José C., Bikker, Hennie, Kempers, Marlies J.E., van Trotsenburg, A.S. Paul, Baas, Frank, de Vijlder, Jan J.M., Vulsma, Thomas, Ris-Stalpers, C., . (2002) Inactivating Mutations in the Gene for Thyroid Oxidase 2 (THOX2) and Congenital Hypothyroidism. New England Journal of Medicine 347:2, 95-102
Full Text37
Annette Grüters, Anja Jenner, Heiko Krude. (2002) Long-term consequences of congenital hypothyroidism in the era of screening programmes. Best Practice & Research Clinical Endocrinology & Metabolism 16:2, 369-382
CrossRef38
L.I. Al-Gazali, Z. Hamid, J. Hertecant, M. Bakir, D. Nath, A. Kakadekar. (2002) An autosomal recessive syndrome of choanal atresia, hypothelia/athelia and thyroid gland anomalies overlapping Bamforth syndrome, ANOTHER syndrome and methimazole embryopathy. Clinical Dysmorphology 11:2, 79-85
CrossRef39
Joachim Pohlenz, Alexandra Dumitrescu, Dorothee Zundel, Ursula Martiné, Winfried Schönberger, Eugene Koo, Roy E. Weiss, Ronald N. Cohen, Shioko Kimura, Samuel Refetoff. (2002) Partial deficiency of Thyroid transcription factor 1 produces predominantly neurological defects in humans and mice. Journal of Clinical Investigation 109:4, 469-473
CrossRef40
Heiko Krude, Barbara Schütz, Heike Biebermann, Arpad von Moers, Dirk Schnabel, Heidi Neitzel, Holger Tönnies, Dagmar Weise, Antony Lafferty, Siegfried Schwarz, Mario DeFelice, Andreas von Deimling, Frank van Landeghem, Roberto DiLauro, Annette Grüters. (2002) Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. Journal of Clinical Investigation 109:4, 475-480
CrossRef41
Roberto Di Lauro. 2002. Thyroid Transcription Factor-1 (TTF-1). .
CrossRef42
P. Bretones, L. Duprez, J. Parma, M. David, G. Vassart, P. Rodien. (2001) A Familial Case of Congenital Hypothyroidism Caused by a Homozygous Mutation of the Thyrotropin Receptor Gene. Thyroid 11:10, 977-980
CrossRef43
Mary P. Gillam, Peter Kopp. (2001) Genetic regulation of thyroid development. Current Opinion in Pediatrics 13:4, 358-363
CrossRef44
Deepak Kamnasaran, Patricia C. M. O'Brien, Simone Schuffenhauer, Oliver Quarrell, James R. Lupski, Paola Grammatico, Malcolm A. Ferguson-Smith, Diane W. Cox. (2001) Defining the breakpoints of proximal chromosome 14q rearrangements in nine patients using flow-sorted chromosomes. American Journal of Medical Genetics 102:2, 173-182
CrossRef45
David Warburton, Margaret Schwarz, Denise Tefft, Guillermo Flores-Delgado, Kathryn D. Anderson, Wellington V. Cardoso. (2000) The molecular basis of lung morphogenesis. Mechanisms of Development 92:1, 55-81
CrossRef46
Takeo Kuribayashi, Akira Hishinuma, Sanae Kanazawa, Yuko Nihei, Megumi Hoshi, Mariko Oyama, Akihisa Nitta, Tamio Ieiri, Osamu Arisaka. (2000) Sequence Analysis of Thyroid Transcription Factor-2 (TTF-2) Gene in Ten Patients with Congenital Hypothyroidism due to Thyroid Dysgenesis.. Clinical Pediatric Endocrinology 9:1, 37-40
CrossRef47
Luca Chiovato, Paola Lapi, Mariastella Zannini, Roberto Di Lauro. (1999) Congenital hypothyroidism: searching for its genetic basis. Current Opinion in Endocrinology & Diabetes 6:4, 277
CrossRef48
Anne-Karina T Perl, Jeffrey A Whitsett. (1999) Molecular mechanisms controlling lung morphogenesis. Clinical Genetics 56:1, 14-27
CrossRef49
Paolo E Macchia, Mario De Felice, Roberto Di Laurot. (1999) Molecular genetics of congenital hypothyroidism. Current Opinion in Genetics & Development 9:3, 289-294
CrossRef50
David Warburton, Matt K. Lee. (1999) Current concepts on lung development. Current Opinion in Pediatrics 11:3, 188-192
CrossRef51
Anne-Karina T Perl, Jeffrey A Whitsett. (1999) Molecular mechanisms controlling lung morphogenesis. Section Editor: Roderick R McInnes e-mail: mcinnes@sickkids.on.ca. Clinical Genetics 57:s1, 14-27
CrossRef52
David Warburton, Carol Wuenschell, Guillermo Flores-Delgado, Kathryn Anderson. (1998) Commitment and differentiation of lung cell lineages. Biochemistry and Cell Biology 76:6, 971-995
CrossRef
