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Endocrine
Published in: Endocrine 3/2010

01-12-2010 | Original Article

Clinical, biochemical, and molecular findings in Argentinean patients with goitrous congenital hypothyroidism

Authors: Ana Chiesa, Carina M. Rivolta, Héctor M. Targovnik, Laura Gruñeiro-Papendieck

Published in: Endocrine | Issue 3/2010

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Abstract

We describe the clinical, biochemical, and molecular findings of a cohort of Argentinean patients with congenital hypothyroidism (CH) and goiter studied to characterize iodide organification and thyroglobulin (TG) defects. 20 CH patients (16 unrelated) were grouped according to serum TG levels and a perchlorate discharge test (PDT) in: group 1 (G1): nine patients with high TG and PDT > 10% who were studied for tiroperoxidase (TPO), dual oxidase 2 (DUOX2), and dual oxidase A2 (DUOXA2) defects and group 2 (G2): 11 patients with low TG and PDT < 10% studied for TG defects. Goiter characteristics, outcome, and TT4 and TT3 levels without treatment were compared between groups. 6/9 G1 patients harbored mutations in TPO gene and 3/9 in DUOX2 gene. In G2, mutations of TG gene were found in 3/11 homozygous, 5/11 compound heterozygous, and 3/11 heterozygous patients. Goiter was only evidenced by thyroid scan in the neonatal period in both groups; was moderately enlarged in patients diagnosed during infancy. In the late detected patients, goiter was big and nodular in G1 while diffuse and moderate in G2. Early detected patients grew and developed normally while those diagnosed late were severely mentally retarded in G1 and only mildly retarded in G2. Thyroid hormone levels of G1 were significantly lower than those of G2 P < 0.01. Molecular approach to characterize defects in organification and TG defects was optimized by TG measurements and PDT. Clinical and biochemical differences based on molecular findings will allow further investigations on genotype–phenotype relationships.
Literature
1.
A. Grüters, H. Biebermann, H. Krude, Neonatal thyroid disorders. Horm. Res. 59(suppl 1), 24–29 (2003)PubMed
2.
A. Grüters, R. Finke, H. Krude, H. Meinhold, Etiological grouping of permanent congenital hypothyrroidism with thyroid gland in situ. Horm. Res. 41, 3–9 (1994)PubMed
3.
4.
W. Osler, Sporadic cretinism in America Trans Congress. Am. Physicians Surg. 4, 169–206 (1897)
5.
J. Stanbury, A. Hedge, A study of a family of goitrous cretins. J. Clin. Endocrinol. Metab. 10, 1471–1475 (1950)CrossRefPubMed
6.
M.J. Abramowicz, H.M. Targovnik, V. Varela, P. Cochaux, L. Krawiec, M.A. Pisarev, F.V.E. Propato, G. Juvenal, H.A. Chester, G. Vassart, Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter. J. Clin. Invest. 90, 1200–1204 (1992)CrossRefPubMed
7.
A. Grüters, B. Kohler, A. Wolf, A. Soling, L. de Vijlder, H. Krude, H. Biebermann, Screening for mutations of the human thyroid peroxidase gene in patients with congenital hypothyroidism. Exp. Clin. Endocrinol. Diabetes 104 (Suppl. 4), 121–123 (1996)
8.
G. Medeiros-Neto, M.J. Gil-Da-Costa, C.L.S. Santos, A.M. Medina, J. Costa e Silva, R.M. Tsou, M. Sobrinho-Simoes, Metastatic thyroid carcinoma arising from congenital goiter due to mutation in the thyroperoxidase gene. J. Clin. Endocrinol. Metab. 83, 4162–4166 (1998)CrossRefPubMed
9.
S. Pannain, R.E. Weiss, C.E. Jackson, D. Dian, J.C. Beck, V.C. Sheffield, N. Cox, S. Refetoff, Two different mutations in the thyroid peroxidase gene of a large inbred Amish kindred: power and limits of homozygosity mapping. J. Clin. Endocrinol. Metab. 84, 1061–1071 (1999)CrossRefPubMed
10.
C.L.S. Santos, H. Bikker, K.G.M. Rego, A.C. Nascimiento, M. Tambascia, J.J.M. de Vijlder, G. Medeiros-Neto, A novel mutation in the TPO gene in goitrous hypothyroid patients with iodide organification defect. Clin. Endocrinol. (Oxf) 51, 165–172 (1999)CrossRef
11.
B. Bakker, H. Bikker, T. Vulsma, J.S.E. de Randamie, B.M. Wiedijk, J.J.M. de Vijlder, Two decades of screening for congenital hypothyroidism in the Netherlands : TPO gene mutations in total iodide organification defect (an update). J. Clin. Endocrinol. Metab. 85, 3708–3712 (2000)CrossRefPubMed
12.
P. Ambrugger, I. Stoeva, H. Biebermann, T. Torresani, C. Leitner, A. Grüters, Novel mutations of the thyroid peroxidase gene in patients with permanent congenital hypothyroidism. Eur. J. Endocrinol. 145, 19–24 (2001)CrossRefPubMed
13.
C.M. Rivolta, S.A. Esperante, L. Gruñeiro-Papendick, A. Chiesa, C.M. Moya, S. Domené, V. Varela, H. Targovnik, Five novel inactivating mutations in the human thyroid peroxidase gene responsible for congenital goiter and iodide organification defect. Hum. Mutat. 22, 259 (2003)CrossRefPubMed
14.
L. Fugazzola, N. Cerutti, D. Mannavola, G. Vannucchi, C. Fallini, L. Persani, P. Beck-Peccoz, Monoallelic expression of mutant thyroid peroxidase allele causing total iodide organification defect. J. Clin. Endocrinol. Metab. 88, 3264–3271 (2003)CrossRefPubMed
15.
C. Rodrigues, P. Jorge, J.P. Soares, I. Santos, R. Salomão, M. Madeira, R.V. Osório, R. Santos, Mutation screening of the thyroid peroxidase gene in a cohort of 55 Portuguese patients with congenital hypothyroidism. Eur. J. Endocrinol. 152, 193–198 (2005)CrossRefPubMed
16.
N. Pfarr, T.J. Musholt, P.B. Musholt, R. Brzezinska, J. Pohlenz, Congenital primary hypothyroidism with subsequent adenomatous goiter in a Turkish patient caused by a homozygous 10-bp deletion in the thyroid peroxidase (TPO) gene. Clin. Endocrinol. (Oxf) 64, 514–518 (2006)CrossRef
17.
C.M. Rivolta, M. Louis-Tisserand, V. Varela, L. Gruñeiro-Papendieck, A. Chiesa, R. González-Sarmiento, H.M. Targovnik, Two compound heterozygous mutations (c.215delA/c.2422T→C and c.387delC/c.1159G→A) in the thyroid peroxidase gene responsible for congenital goitre and iodide organification defect. Clin. Endocrinol. (Oxf) 67, 238–246 (2007)CrossRef
18.
J. Deladoëy, N. Pfarr, J.-M. Vuissoz, J. Parma, G. Vassart, S. Biesterfeld, J. Pohlenz, G. Van Vliet, Pseudodominant inheritance of goitrous congenital hypothyroidism caused by TPO mutations: Molecular and in silico studies. J. Clin. Endocrinol. Metab. 93, 627–633 (2008)CrossRefPubMed
19.
J.C. Moreno, H. Bikker, M.J.E. Kempers, A.S.P. van Trotsenburg, F. Baas, J.J.M. de Vijlder, T. Vulsma, C. Ris-Stalpers, Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. N. Engl. J. Med. 347, 95–102 (2002)CrossRefPubMed
20.
M.C. Vigone, L. Fugazzola, I. Zamproni, A. Passoni, S. Di Candia, G. Chiumello, L. Persani, G. Weber, Persistent mild hypothyroidism associated with novel sequence variants of the DUOX2 gene in two siblings. Hum. Mutat. 26, 395 (2005)CrossRefPubMed
21.
V. Varela, C.M. Rivolta, S.A. Esperante, G. Gruñeiro-Papendieck, A. Chiesa, H.M. Targovnik, Three mutations (p.Q36H, p.G418fsX482, and g.IVS19–2A&gt;C) in the dual oxidase 2 gene responsible for congenital goiter and iodide organification defect. Clin. Chem. 52, 182–191 (2006)CrossRefPubMed
22.
N. Pfarr, E. Korsch, S. Kaspers, A. Herbst, A. Stach, C. Zimmer, J. Pohlenz, Congenital hypothyroidism caused by new mutations in the thyroid oxidase 2 (THOX2) gene. Clin. Endocrinol. (Oxf) 65, 810–815 (2006)CrossRef
23.
Y. Maruo, H. Takahashi, I. Soeda, N. Nishikura, K. Matsui, Y. Ota, Y. Mimura, A. Mori, H. Sato, Y. Takeuchi, Transient congenital hypothyroidism caused by biallelic mutations of the dual oxidase 2 gene in Japanese patients detected by a neonatal screening program. J. Clin. Endocrinol. Metab. 93, 4261–4267 (2008)CrossRefPubMed
24.
I. Zamproni, H. Grasberger, F. Cortinovis, M.C. Vigone, G. Chiumello, S. Mora, K. Onigata, L. Fugazzola, S. Refetoff, L. Persani, G. Weber, Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism. J. Clin. Endocrinol. Metab. 93, 605–610 (2008)CrossRefPubMed
25.
P. Kopp, Pendred syndrome and genetic defects in thyroid hormone synthesis. Rev. Endocr. Metab. Disord. 1, 109–121 (2000)CrossRefPubMed
26.
H.M. Targovnik, S.A. Esperante, C.M. Rivolta, Genetics and phenomics of hypothyroidism and goiter due to thyroglobulin mutations. Mol. Cell. Endocrinol. 322, 44–55 (2010)CrossRefPubMed
27.
T. Ieiri, P. Cochaux, H.M. Targovnik, M. Suzuki, S.-I. Shimoda, J. Perret, G. Vassart, A 3′ splice site mutation in the thyroglobulin gene responsible for congenital goiter with hypothyroidism. J. Clin. Invest. 88, 1901–1905 (1991)CrossRefPubMed
28.
H.M. Targovnik, G. Medeiros-Neto, V. Varela, P. Cochaux, B.L. Wajchenberg, G. Vassart, A nonsense mutation causes human hereditary congenital goiter with preferential production of a 171-nucleotide-deleted thyroglobulin ribonucleic acid messenger. J. Clin. Endocrinol. Metab. 77, 210–215 (1993)CrossRefPubMed
29.
S.A.R. van de Graaf, C. Ris-Stalpers, G.J.M. Veenboer, M. Cammenga, C. Santos, H.M. Targovnik, J.J.M. de Vijlder, G. Medeiros-Neto, A premature stopcodon in thyroglobulin mRNA results in familial goiter and moderate hypothyroidism. J. Clin. Endocrinol. Metab. 84, 2537–2542 (1999)CrossRefPubMed
30.
H.M. Targovnik, C.M. Rivolta, F.M. Mendive, C.M. Moya, G. Medeiros-Neto, Congenital goiter with hypothyroidism caused by a 5′ splice site mutation in the thyroglobulin gene. Thyroid 11, 685–690 (2001)CrossRefPubMed
31.
P. Caron, C.M. Moya, D. Malet, V.J. Gutnisky, B. Chabardes, C.M. Rivolta, H.M. Targovnik, Compound heterozygous mutations in the thyroglobulin gene (1143delC and 6725G>A[R2223H]) resulting in fetal goitrous hypothyroidism. J. Clin. Endocrinol. Metab. 88, 3546–3553 (2003)CrossRefPubMed
32.
V.J. Gutnisky, C.M. Moya, C.M. Rivolta, S. Domené, V. Varela, J.V. Toniolo, G. Medeiros-Neto, H.M. Targovnik, Two distinct compound heterozygous constellation (R277X/IVS34–1G&gt;C and R277X/R1511X) in the thyroglobulin (TG) gene in affected individuals of a brazilian kindred with congenital goiter and defective TG synthesis. J. Clin. Endocrinol. Metab. 89, 646–657 (2004)CrossRefPubMed
33.
C.M. Rivolta, C.M. Moya, V.J. Gutnisky, V. Varela, J.M. Miralles-García, González-R. Sarmiento, H.M. Targovnik, A new case of congenital goiter with hypothyroidism due to a homozygous p.R277X mutation in the exon 7 of the thyroglobulin gene: a mutational hot spot could explain the recurrence of this mutation. J. Clin. Endocrinol. Metab. 90, 3766–3770 (2005)CrossRefPubMed
34.
A. Hishinuma, S. Fukata, K. Kakudo, Y. Murata, T. Ieiri, High incidence of thyroid cancer in long-standing goiters with thyroglobulin mutations. Thyroid 15, 1079–1084 (2005)CrossRefPubMed
35.
S. Kitanaka, A. Takeda, U. Sato, Y. Miki, A. Hishinuma, T. Ieiri, T. Igarashi, A novel compound heterozygous mutation in the thyroglobulin gene resulting in congenital goitrous hypothyroidism with high serum triiodothyronine levels. J. Hum. Genet. 51, 379–382 (2006)CrossRefPubMed
36.
A. Hishinuma, S. Fukata, S. Nishiyama, Y. Nishi, M. Oh-Ishi, Y. Murata, Y. Ohyama, N. Matsuura, K. Kasai, S. Harada, S. Kitanaka, J. Takamatsu, K. Kiwaki, H. Ohye, T. Uruno, C. Tomoda, T. Tajima, K. Kuma, A. Miyauchi, T. Ieiri, Haplotype analysis reveals founder effects of thyroglobulin gene mutations C1058R and C1977S in Japan. J. Clin. Endocrinol. Metab. 91, 3100–3104 (2006)CrossRefPubMed
37.
M. Caputo, C.M. Rivolta, S.A. Esperante, L. Gruñeiro-Papendieck, A. Chiesa, C.G. Pellizas, R. González-Sarmiento, H.M. Targovnik, Congenital hypothyroidism with goitre caused by new mutations in the thyroglobulin gene. Clin. Endocrinol. (Oxf) 67, 351–357 (2007)CrossRef
38.
M. Caputo, C.M. Rivolta, V.J. Gutnisky, L. Gruñeiro-Papendieck, A. Chiesa, G. Medeiros-Neto, R. González-Sarmiento, H.M. Targovnik, Recurrence of the p.R277X/p.R1511X compound heterozygous mutation in the thyroglobulin gene in unrelated families with congenital goiter and hypothyroidism: haplotype analysis using intragenic thyroglobulin polymorphisms. J. Endocrinol. 195, 167–177 (2007)CrossRefPubMed
39.
Y. Kanou, A. Hishinuma, K. Tsunekawa, K. Seki, Y. Mizuno, H. Fujisawa, T. Imai, Y. Miura, T. Nagasaka, C. Yamada, T. Ieiri, M. Murakami, Y. Murata, Thyroglobulin gene mutations producing defective intracellular transport of thyroglobulin are associated with increased thyroidal type 2 iodothyronine deiodinase activity. J. Clin. Endocrinol. Metab. 92, 1451–1457 (2007)CrossRefPubMed
40.
V. Pardo, J. Vono-Toniolo, I.G.S. Rubio, M. Knobel, R.F. Possato, H.M. Targovnik, P. Kopp, G. Medeiros-Neto, The p.A2215D thyroglobulin gene mutation leads to deficient synthesis and secretion of the mutated protein and congenital hypothyroidism with wide phenotype variation. J. Clin. Endocrinol. Metab. 94, 2938–2944 (2009)CrossRefPubMed
41.
D.M. Niu, J.H. Hsu, K.W. Chong, C.H. Huang, Y.H. Lu, C.H. Kao, H.C. Yu, M.Y. Lo, T.S. Jap, Six new mutations of the thyroglobulin gene discovered in Taiwanese children presenting with thyroid dyshormonogenesis. J. Clin. Endocrinol. Metab. 94, 5045–5052 (2009)CrossRefPubMed
42.
G.A. Machiavelli, M. Caputo, C.M. Rivolta, M.C. Olcese, L. Gruñeiro-Papendieck, A. Chiesa, R. González-Sarmiento, H.M. Targovnik, Molecular analysis of congenital goitres with hypothyroidism caused by defective thyroglobulin synthesis. Identification of a novel c.7006C>T [p.R2317X] mutation and expression of minigenes containing nonsense mutations in exon 7. Clin. Endocrinol. (Oxf) 72, 112–121 (2010)CrossRef
43.
H.M. Targovnik, P.F. Souchon, G.A. Machiavelli, A.S. Salmon-Musial, P.L. Mauran, V. Sulmont, M. Doco-Fenzy, C.M. Rivolta, Congenital goitre with hypothyroidism caused by a novel compound heterozygous mutations in the thyroglobulin gene. Clin. Endocrinol. (Oxf) 72, 176–178 (2010)CrossRef
44.
D. Peteiro-Gonzalez, J. Lee, J. Rodriguez-Fontan, I. Castro-Piedras, J. Cameselle-Teijeiro, A. Beiras, S.B. Bravo, C.V. Alvarez, D.M. Hardy, H.M. Targovnik, P. Arvan, J. Lado-Abeal, New insights into thyroglobulin pathophysiology revealed by the study of a family with congenital goiter. J. Clin. Endocrinol. Metab. 95, 3522–3526 (2010)CrossRefPubMed
45.
J.C. Moreno, W. Klootwijk, H. van Toor, G. Pinto, M. D’Alessandro, A. Leger, D. Goudie, M. Polak, A. Gruters, T.J. Visser, Mutations in the iodotyrosine deiodinase gene and hypothyroidism. N. Engl. J. Med. 358, 1811–1818 (2008)CrossRefPubMed
46.
G. Afink, W. Kulik, H. Overmars, J. de Randamie, T. Veenboer, A. van Cruchten, M. Craen, C. Ris-Stalpers, Molecular characterization of iodotyrosine dehalogenase deficiency in patients with hypothyroidism. J. Clin. Endocrinol. Metab. 93, 4894–4901 (2008)CrossRefPubMed
47.
S. Rose, R. Brown, T. Foley, P.B. Kaplowitz, C.I. Kaye, S. Sundararajan, S. Varma, Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 117, 2290–2303 (2006)CrossRefPubMed
48.
P. Cavarzere, M. Castanet, M. Polak, M.C. Raux-Demay, S. Cabrol, J.C. Carel, J. Leger, P. Czernichow, Clinical description of infants with congenital hypothyroidism and iodide organification defects. Horm. Res. 70, 240–248 (2008)CrossRefPubMed
Metadata
Title
Clinical, biochemical, and molecular findings in Argentinean patients with goitrous congenital hypothyroidism
Authors
Ana Chiesa
Carina M. Rivolta
Héctor M. Targovnik
Laura Gruñeiro-Papendieck
Publication date
01-12-2010
Publisher
Springer US
Published in
Endocrine / Issue 3/2010
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-010-9391-8

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