This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kopp, P. Search for Related Content PubMed PubMed Citation Articles by Kopp, P.

Perspective: Genetic Defects in the Etiology of Congenital Hypothyroidism

Division of Endocrinology, Metabolism & Molecular Medicine, Northwestern University, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: Peter Kopp, M.D., Division of Endocrinology, Metabolism & Molecular Medicine, Northwestern University, Tarry 15, 303 East Chicago Avenue, Chicago, Illinois 60611. E-mail: . p-kopp{at}northwestern.edu

	Abstract

Top Abstract Introduction Hypothalamic and pituitary... Genetic defects in thyroid... Resistance to TSH Genetic defects in thyroid... Defects in thyroid hormone... Perspective References

 
Congenital hypothyroidism affects about 1:3000 to 1:4000 infants and may be caused by defects in thyroidal ontogeny or hormone synthesis. The impressive advances in molecular genetics led to the characterization of numerous genes that are essential for normal development and hormone production of the hypothalamic-pituitary-thyroid axis. Mutations in many of these genes now provide a molecular explanation for a subset of the sporadic and familial forms of congenital hypothyroidism.

Defects in one of the multiple steps required for normal hormone synthesis account for about 10% of cases with congenital hypothyroidism. They are typically recessive and therefore more common in inbred families. In the vast majority of patients, congenital hypothyroidism is sporadic and associated with thyroid dysgenesis, a spectrum of developmental defects, which includes the absence of detectable thyroid tissue, ectopic tissue, and thyroid hypoplasia. The molecular defects known to date only explain a minority of these cases and include mutations in the paired box transcription factor PAX8, and the thyroid transcription factors TTF1 and TTF2. It is likely that a further subset of patients with thyroid dysgenesis have defects in other transacting proteins or elements of the signaling pathways controlling growth and function of thyrocytes. In other instances, thyroid dysgenesis may be a polygenic disease or have a multifactorial basis. Aside from providing fundamental insights into the ontogeny and the pathophysiology of the thyroid, the characterization of the molecular basis of congenital hypothyroidism may have growing importance for genetic testing and counseling in the future.

	Introduction

Top Abstract Introduction Hypothalamic and pituitary... Genetic defects in thyroid... Resistance to TSH Genetic defects in thyroid... Defects in thyroid hormone... Perspective References

 
Normal thyroid function is essential for development, growth and metabolic homeostasis. The prerequisites for an euthyroid metabolic state include a normally developed thyroid gland, a properly functioning system for thyroid hormone synthesis, and adequate iodine intake. In iodine sufficient regions, permanent congenital hypothyroidism affects about 1:3000 to 1:4000 newborns, and it is one of the most common preventable causes of mental retardation (1).

In about 10% of all cases, congenital hypothyroidism is the consequence of defects in one of the steps of thyroid hormone synthesis, inborn errors of metabolism referred to as dyshormogenesis. A heterogeneous group of developmental abnormalities, thyroid dysgenesis, accounts for about 85% of all cases with congenital hypothyroidism. These anomalies include thyroid (hemi)agenesis, ectopic thyroid tissue, cysts of the thyroglossal duct, and thyroid hypoplasia (2, 3). In the vast majority of all cases, thyroid dysgenesis is sporadic, but in about 2% it is familial (4), an observation supporting the possibility of a genetic etiology. The higher prevalence of thyroid dysgenesis in Hispanics and Caucasians in comparison to Blacks, the predominance of thyroid dysgenesis in girls, and the higher prevalence of associated malformations also suggest the presence of genetic factors in the pathogenesis of congenital hypothyroidism (5). More recently, detailed analyses of familial and sporadic patients with congenital hypothyroidism, with or without associated phenotypic features, have unraveled the molecular basis in a small fraction of these patients (2, 3). In the remaining 5% of cases, the hypothyroidism is thought to result from the transplacental transfer of maternal antibodies to the child.

	Hypothalamic and pituitary defects resulting in hypothyroidism

Top Abstract Introduction Hypothalamic and pituitary... Genetic defects in thyroid... Resistance to TSH Genetic defects in thyroid... Defects in thyroid hormone... Perspective References

 
Several clinical reports have suggested isolated TRH deficiency as a cause of central hypothyroidism (6, 7), but there are currently no reports on patients with documented defects in the TRH gene. Mice with targeted disruption of the Trh gene are hypothyroid and, rather surprisingly, their TSH is elevated, but its biological activity is reduced (8). Similar biochemical constellations with elevated TSH of reduced bioactivity have been reported in some individuals with central hypothyroidism (9) (see Table 1).

Isolated hereditary TSH deficiency is a rare cause of central hypothyroidism and can be caused by recessive mutations in the TSHß chain (11, 12). In these patients, TSH is unmeasurable or very low, and the administration of TRH does not result in a rise in serum TSH. The levels and the function of the other pituitary hormones are normal, including an adequate rise of PRL in response to TRH. Among the five currently known mutations, some are recurrent in certain populations suggesting a founder effect, whereas others have been found independently in sporadic and familial patients from different ethnic origins. A subset of these mutations is predicted to disrupt heterodimerization with the glycoprotein hormone -chain, whereas others lead to premature truncations (12, 13).

Genetic defects in the development and function of the pituitary gland can result in various forms of combined pituitary hormone deficiency (CPHD). Patients with CPHD present with impaired production and secretion of one or several anterior pituitary hormones that may include TSH. CPHD has been documented in patients with mutations in four transcription factors involved in pituitary development and hormone expression (POU1F1, PROP1, LHX3, HESX1) (14, 15, 16, 17, 18). Many of these discoveries were preceded by the molecular analysis of inbred mouse strains or mice with targeted disruption of these genes. Mutations in the pituitary-specific transcription POU1F1 (PIT1) result in deficiencies of GH, PRL, and TSH. Depending on the location of the mutation, the mode of transmission is recessive or dominant. PROP1 (Prophet of PIT1) is a paired-like homeodomain factor acting upstream of POU1F1 and its recessive inactivation disrupts the ontogenesis, differentiation, and function of somatotropes, lactotropes, thyrotropes, and gonadotropes. There is, however, variability in the phenotypic expression among CPHD patients with the same or distinct PROP-1 mutations (19). Recessive mutations in LHX3, a LIM homeodomain transcription factor, also cause CPHD of all anterior pituitary hormones with the exception of ACTH (16). In addition, these patients have a rigid cervical spine and a limited ability to rotate the head (16). Familial septo-optic dysplasia, a syndromic form of CPHD associated with optic nerve hypoplasia and agenesis of midline structures in the brain, can be caused by homozygous mutations in HESX1 (or RPX/Rathke pouch homeobox), a paired-like class of homeobox transcription factors (17). The observation that a small proportion of mice heterozygous for a Hesx1 null allele has a milder form of septo-optic dysplasia prompted further screening of patients presenting with a wide spectrum of congenital pituitary dysfunctions. A subset of these patients was indeed found to be heterozygous for HESX1 mutations (18). Heterozygous HESX1 mutations result in various constellations of pituitary hormone deficiencies, and the phenotype is variable among family members with the same mutation.

	Genetic defects in thyroid development

Top Abstract Introduction Hypothalamic and pituitary... Genetic defects in thyroid... Resistance to TSH Genetic defects in thyroid... Defects in thyroid hormone... Perspective References

 
The mature mammalian thyroid gland evolves from two distinct embryologic structures, the thyroid diverticulum, an endodermal component that gives rise to thyroid follicular cells, and the neuroectodermal ultimobranchial bodies that differentiate into the parafollicular calcitonin-producing C cells. Following migration and fusion of the two cell populations, thyroid follicular cells undergo further differentiation that is characterized by the expression of genes that are essential for thyroid hormone synthesis such as the TSH receptor, the sodium-iodide symporter, thyroperoxidase (TPO), and thyroglobulin (TG). Thyroid hormone is detectable in the fetus at about gestational wk 11.

During the last few years, it has become apparent that mutations in transcription factors that govern thyroid development and gene expression may result in syndromic and nonsyndromic forms of thyroid dysgenesis, and these observations are corroborated by similar observation in murine knockout models (20, 21, 22, 23).

Heterozygous mutations in PAX8, a paired domain transcription factor involved in thyroid development and expression of the TPO and TG genes (24), have been documented and characterized in sporadic and familial patients with thyroid hypoplasia or ectopy (20, 25, 26). It is currently unclear why mutation of a single PAX8 allele is sufficient to result in congenital hypothyroidism in humans, a finding that contrasts with the observation that mice heterozygous for a disrupted Pax8 locus do not display a pathological phenotype (21). In humans, the biochemical and morphological phenotype may vary among patients with the same PAX8 mutation (20, 26). Underlying mechanisms may include incomplete penetrance, a phenomenon associated with mutations in other PAX genes. Alternatively, the phenotypic expression may be modulated by modifier genes.

Homozygosity for recessive mutations in the forkhead/winged-helix domain transcription factor FKLH15, commonly referred to TTF2, results in a syndromic form of thyroid dysgenesis with the eponym Bamforth-Lazarus syndrome (22, 27). This phenotype, described in two brothers from a consanguineous family, includes thyroid agenesis, cleft palate, choanal atresia, bifid epiglottis, and spiky hair (22, 27). Mice homozygous for a disrupted Ttf2 gene die shortly after birth and are profoundly hypothyroid (23). They exhibit either small lingual thyroid remnants or have complete thyroid agenesis, and they also have cleft palates. These findings support the important role of TTF2, which is also involved in transcriptional control of the TG and the TPO gene promoters (28), in thyroid development.

Thyroid transcription factor 1 (NKX2A, TITF-1, TTF1, or thyroid specific enhancer-binding protein T/ebp) is a homeobox domain transcription factor of the NKX2 family involved in the development of the gland and in transcriptional control of the TG, TPO, and TSH receptor genes (24). It is also expressed in the lung, the forebrain and the pituitary gland. Mice with targeted disruption of both TTF1 alleles survive throughout gestation, but die at birth from respiratory failure (29). The lung is severely hypoplastic and consists of a sac-like structure without bronchioli, alveoli or lung parenchyma (29). Both the thyroid gland and pituitary gland are completely absent, and the hypothalamus is severely malformed. Several screenings of patients with thyroid dysgenesis for mutations in the TTF1 gene were negative. The observation of a newborn with severe respiratory distress, a normally located thyroid gland and elevated TSH levels and a heterozygous deletion on chromosome 14q13 encompassing the TTF1 locus suggested that haploinsufficiency for TTF1 could be associated with impaired lung maturation and thyroid function (30). The detection of a similar heterozygous deletion of chromosome 14q12–13.3 in two female siblings with congenital thyroid dysfunction and recurrent acute respiratory distress gave further support to this concept (31). Very recently, a few additional patients with hyperthyrotropinemia, neonatal respiratory distress and ataxia associated with missense or frameshift mutations, or chromosomal deletions of the TTF-1 gene have been reported (32, 33). The TSH levels were only mildly elevated and the thyroid was normal in size and position. The hallmark of this phenotype is the neurologic deficit, which includes ataxia or choreoathetosis, truncal apraxia, mental retardation, and neonatal respiratory distress (32, 33).

	Resistance to TSH

Top Abstract Introduction Hypothalamic and pituitary... Genetic defects in thyroid... Resistance to TSH Genetic defects in thyroid... Defects in thyroid hormone... Perspective References

 
The response to bioactive TSH may be impaired at the level of the thyroid follicular cells. Total insensitivity to TSH results in a small hypoplastic thyroid gland and reduced synthesis and secretion of thyroid hormones. Of note, a similar morphologic and biochemical phenotype may occur in patients with mutations in PAX8 and emphasizes the limitations of morphologic criteria. Resistance to TSH may be caused by various molecular mechanisms.

In a subset of these patients, the molecular cause consists of mutations in the TSH receptor that are partially or completely inactivating (34, 35, 36, 37). In partial resistance, TSH is elevated, but the peripheral hormone levels are normal, a constellation referred to as euthyroid hyperthyrotropinemia (34). In these patients, the size of the thyroid is normal or enlarged. Homozygous or compound heterozygous inactivating mutations in the TSH receptor have been found in several patients with overt hypothyroidism and thyroid hypoplasia (35, 36, 37), as well as in the thoroughly characterized hyt/hyt mouse that is severely hypothyroid and has a normally located, hypoplastic gland (38). Because of absent tracer uptake in scintigraphic studies, several of these patients were initially diagnosed with thyroid agenesis, but careful ultrasonographic evaluation revealed the presence of hypoplastic thyroid tissue. TG levels are thought to be a useful marker for demonstrating the presence of thyroid tissue in neonates. However, the TG levels in patients with thyroid hypoplasia associated with TSH receptor mutations were undetectable, normal, or elevated.

The hallmark of pseudohypoparathyroidism Ia consists of resistance to PTH. However, patients with this disorder may also exhibit resistance to the glycoprotein hormones TSH, LH, and FSH (39). In addition to the clinical and biochemical features related to hormone resistance, these patients have characteristic skeletal and developmental abnormalities such as short stature, brachydactyly and ectopic calcifications (Albright’s hereditary osteodystrophy) (39). The unresponsiveness to these hormones in pseudohypoparathyroidism Ia is the consequence of mutations in the maternal copy of the GNAS1 (Gs subunit) gene, in combination with tissues-specific imprinting (39). If the mutation is transmitted on the paternal allele, the phenotype is limited to Albright’s hereditary osteodystrophy (39).

Unresponsiveness to TSH can also be inherited as an autosomal dominant trait, but the molecular defect remains to be defined (40).

	Genetic defects in thyroid hormone synthesis

Top Abstract Introduction Hypothalamic and pituitary... Genetic defects in thyroid... Resistance to TSH Genetic defects in thyroid... Defects in thyroid hormone... Perspective References

 
Normal iodide uptake at the basolateral membrane by the perchlorate-sensitive sodium/iodide symporter NIS is a rate-limiting step in thyroid hormone synthesis (41, 42, 43), and several homozygous or compound heterozygous mutations have been identified in individuals with hypothyroidism associated with impaired iodide uptake (for review, see Ref. 43). Many of these patients have a diffuse or nodular goiter, little or no uptake of radioiodine, and a decreased saliva/serum radioiodine ratio.

Efflux of iodide at the apical membrane of thyroid follicular cells is at least in part mediated by pendrin (SCL26A4), a member of the Solute Carrier Family 26A (44, 45, 46). Mutations in the SCL26A4 gene cause Pendred’s syndrome, an autosomal recessive disorder traditionally defined by the triad of sensorineural congenital deafness, goiter, and a partially positive perchlorate test. The partial discharge of radioiodine after the administration of perchlorate indicates that the gland has an impaired ability to organify iodide. Although some patients with Pendred’s syndrome present with congenital hypothyroidism (47), the majority of individuals are clinically and biochemically euthyroid, at least under conditions of normal nutritional iodide intake. Furthermore, the prevalence of goiters may be lower in patients with pendrin mutations living in iodine-replete regions (48). Pds knockout mice are profoundly deaf, but they do not display an enlarged thyroid or abnormal thyroid hormone levels (49). It is currently unknown whether they have a partial organification defect (49).

In the follicular lumen, the iodination of tyrosine residues in TG, and the coupling of iodinated tyrosines to generate T₄ and T₃, is dependent on the normal function of the glycosylated hemoprotein TPO. TPO defects are among the most frequent causes of inborn errors of thyroid hormone synthesis. Mutations in the TPO gene have been reported in numerous families with a partial or total organification defect (50, 51, 52). In a recent survey, total iodide organification defects were estimated to occur in approximately 1:66,000 neonates, and the majority of these infants were homozygous or compound heterozygous for mutations in the TPO gene (52). This observation suggests that most patients with a total iodide organification defect harbor inactivating mutations in this gene.

The iodination and coupling reactions are dependent on hydrogen peroxide (H₂O₂) as an essential cofactor. Recently, two NADPH oxidases, THOX1 and THOX2 (also referred to as LNOX or DUOX), that may be part of this system have been cloned (53, 54). Sequence alterations in the THOX2 gene, which is more abundantly expressed at the apical membrane of thyrocytes, were reported in several patients with a total iodide organification defect, but their functional significance remains unclear (55). In a family with two affected siblings presenting with hypothyroidism, goiter, and iodine organification defects, nearly undetectable thyroid NADPH oxidase activities were measured in tissue slices (56). It has been proposed that the cause of the organification defect in these patients is the result of impaired Ca²⁺/NAD(P)H-dependent H₂O₂ generation (56), but the exact molecular defect remains to be defined. Defective H₂O₂ generation has also been thought to explain the phenotype in some individuals with euthyroid goiter and abnormal iodide organification (3).

TG, a homodimeric glycoprotein, is a key element in thyroid hormone synthesis and storage. It is encoded by a very large gene spanning more than 300 kb and containing 48 exons (for recent reviews, see Refs. 57 and 58). Mutations in the TG gene have been reported in a number of animal models and human patients (58, 59). Unless treated with levothyroxine, these patients typically present with goiter in early childhood. The metabolic status is variable and, depending on the severity of the defect, the patients are hypothyroid, subclinically hypothyroid, or euthyroid. The serum TG levels may be low, normal, or elevated. The radioiodine uptake is elevated. TG defects are usually transmitted in an autosomal recessive manner; however, an autosomal dominant mode of inheritance has been proposed in one kindred (60).

Molecular analysis of several TG mutations found in patients with congenital hypothyroidism and in the cog/cog mouse, which all present with goiters, reveal that at least some of these alterations result in a secretory defect and thus an endoplasmic reticulum storage disease (61). In contrast to these TG defects associated with goiter development, the recessive dwarf rdw/rdw rat displays a nongoitrous form of congenital primary hypothyroidism caused by a Tg gene mutation (62, 63). The identification of a mutation in the Tg gene as a cause of nongoitrous hypothyroidism in the rdw/rdw rat challenges the previously held generalization that nongoitrous congenital hypothyroidism is caused by thyroid dysgenesis or defects in TSH signaling.

After entering the follicular cell, TG is hydrolyzed, and T₄ and T₃ are secreted into the blood at the basolateral membrane. The iodotyrosines MIT and DIT, which are much more abundant in the TG molecule, are deiodinated by an intrathyroidal dehalogenase and recycled for hormone synthesis. Several patients with leakage of MIT and DIT from the thyroid and urinary secretion of these metabolites have been reported (64). The disorder appears to be inherited in an autosomal recessive fashion. Expression of the phenotype, which may include goiter and hypothyroidism, is thought to be dependent on the nutritional iodide intake. The intrathyroidal dehalogenase has not been characterized at the molecular level.

	Defects in thyroid hormone action

Top Abstract Introduction Hypothalamic and pituitary... Genetic defects in thyroid... Resistance to TSH Genetic defects in thyroid... Defects in thyroid hormone... Perspective References

 
Resistance to thyroid hormone (RTH) is characterized by decreased responsiveness to thyroid hormone (65, 66). Biochemically, the syndrome is defined by elevated free thyroid hormones and an inappropriately normal or elevated level of TSH. The clinical spectrum is highly variable and ranges from isolated biochemical abnormalities to a constellation of features that includes goiter, variable features of hyper- and hypothyroidism, short stature, delayed bone maturation, and attention deficit hyperactivity disorder (65, 67). RTH is most commonly caused by autosomal dominant mutations in TRß that exert a dominant negative effect (65, 66). In one family, RTH was caused by the loss of both TRß alleles (68). More recently, familial cases of RTH without linkage to the TRß locus have been reported indicating the possibility of nonallelic heterogeneity (69, 70).

The diagnosis of RTH is important to avoid inappropriate treatment of the condition (65), and although rare, it is a diagnostic consideration when neonatal screening shows mildly increased TSH levels (71). While asymptomatic patients do not require intervention, treatment may be required in a subset of patients to ameliorate features of hypo- or hyperthyroidism (72).

	Perspective

Top Abstract Introduction Hypothalamic and pituitary... Genetic defects in thyroid... Resistance to TSH Genetic defects in thyroid... Defects in thyroid hormone... Perspective References

 
The isolation and the identification of genes controlling thyroid development and thyroid hormone synthesis continues to provide unique insights into the ontogenesis and physiology of the hypothalamic-pituitary-thyroid axis, as well as a more precise understanding of (congenital) disorders at the molecular level. It has become apparent that thyroid dysgenesis is, at least in part, a genetic disorder. However, the molecular defects known to date only account for a minority of cases of thyroid dysgenesis. It is likely that a further subset of patients with thyroid dysgenesis have defects in other transacting proteins that remain to be discovered. In other instances, thyroid dysgenesis may be a polygenic disease or have a multifactorial basis. Genetic testing is currently of limited importance in patients with congenital hypothyroidism. However, analyses at the molecular level may be useful and informative in familial cases and sporadic patients presenting with additional phenotypic characteristics.

	Acknowledgments

 

	Footnotes

 
Because of space constraints, only selected references could be included in this article, and numerous publications of interest had to be omitted.

Abbreviations: CPHD, Combined pituitary hormone deficiency; PAX8, paired box transcription factor; PROP1, Prophet of Pit1; RTH, resistance to thyroid hormone; TG, thyroglobulin; TPO, thyroperoxidase; TTF, thyroid transcription factor.

Received February 14, 2002.

Accepted for publication February 14, 2002.

	References

Top Abstract Introduction Hypothalamic and pituitary... Genetic defects in thyroid... Resistance to TSH Genetic defects in thyroid... Defects in thyroid hormone... Perspective References

 

1. New England congenital hypothyroidism collaborative 1981 Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestation. Lancet 2:1095–1098[Medline]
2. Gillam MP, Kopp P 2001 Genetic regulation of thyroid development. Curr Opin Pediatr 13:358–363[CrossRef][Medline]
3. Gillam MP, Kopp P 2001 Genetic defects in thyroid hormone synthesis. Curr Opin Pediatr 13:364–372[CrossRef][Medline]
4. Castanet M, Polak M, Bonaiti-Pellie C, Lyonnet S, Czernichow P, Leger J 2001 Nineteen years of national screening for congenital hypothyroidism: familial cases with thyroid dysgenesis suggest the involvement of genetic factors. J Clin Endocrinol Metab 86:2009–2014[Abstract/Free Full Text]
5. Devos H, Rodd C, Gagne N, Laframboise R, Van Vliet G 1999 A search for the possible molecular mechanisms of thyroid dysgenesis: sex ratios and associated malformations. J Clin Endocrinol Metab 84:2502–2506[Abstract/Free Full Text]
6. Niimi H, Inomata H, Sasaki N, Nakajima H 1982 Congenital isolated thyrotrophin releasing hormone deficiency. Arch Dis Child 57:877–878[Medline]
7. Katakami H, Kato Y, Inada M, Imura H 1984 Hypothalamic hypothyroidism due to isolated thyrotropin-releasing hormone (TRH) deficiency. J Endocrinol Invest 7:231–233[Medline]
8. Yamada M, Saga Y, Shibusawa N, Hirato J, Murakami M, Iwasaki T, Hashimoto K, Satoh T, Wakabayashi K, Taketo MM, Mori M 1997 Tertiary hypothyroidism and hyperglycemia in mice with targeted disruption of the thyrotropin-releasing hormone gene. Proc Natl Acad Sci USA 94:10862–10867[Abstract/Free Full Text]
9. Beck-Peccoz P, Amr S, Menezes-Ferreira MM, Faglia G, Weintraub BD 1985 Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone. N Engl J Med 312:1085–1090[Abstract]
10. Collu R, Tang J, Castagné J, Lagacé G, Masson N, Huot C, Deal C, Delvin E, Faccenda E, Eidne KA, van Vliet G 1997 A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene. J Clin Endocrinol Metab 82:1361–1365
11. Hayashizaki Y, Hiraoka Y, Tatsumi Y, Hashimoto T, Furuyama J, Miyai K, Nishijo K, Matsura M, Kohno H, Labbe A, Matsubara K 1990 Deoxyribonucleic acid analysis of five families with familial inherited thyroid stimulating hormone deficiency. J Clin Endocrinol Metab 71:792–796[Abstract]
12. Pohlenz J, Dumitrescu A, Aumann U, Koch G, Melchior R, Prawitt D, Refetoff S 2002 Congenital secondary hypothyroidism caused by exon skipping due to a homozygous donor splice site mutation in the TSHß-subunit gene. J Clin Endocrinol Metab 87:336–339[Abstract/Free Full Text]
13. Medeiros-Neto G, Heodotou DT, Rajan S, Kommareddi S, de Lacerda L, Sandrini R, Boguszewski MCS, Hollenberg AN, Radovick S, Wondisford FE 1996 A circulating, biologically inactive thyrotropin caused by a mutation in the beta subunit gene. J Clin Invest 97:1250–1256[Medline]
14. Radovick S, Nations M, Du Y, Berg LA, Weintraub BD, Wondisford FE 1992 A mutation in the POU-homeodomain of Pit-1 responsible for combined pituitary hormone deficiency. Science 257:1115–1118[Abstract/Free Full Text]
15. Wu W, Cogan JD, Pfäffle RW, Dasen JS, Frisch H, O’Connell SM, Flynn SE, Brown MR, Mullis PE, Parks JS, Phillips JAI, Rosenfeld MG 1998 Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet 18:147–149[CrossRef][Medline]
16. Netchine I, Sobrier ML, Krude H, Schnabel D, Maghnie M, Marcos E, Duriez B, Cacheux V, Moers A, Goossens M, Gruters A, Amselem S 2000 Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet 25:182–186[CrossRef][Medline]
17. Dattani MT, Martinez-Barbera JP, Thomas PQ, Brickman JM, Gupta R, Martensson IL, Toresson H, Fox M, Wales JK, Hindmarsh PC, Krauss S, Beddington RS, Robinson IC 1998 Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 19:125–133[CrossRef][Medline]
18. Thomas PQ, Dattani MT, Brickman JM, McNay D, Warne G, Zacharin M, Cameron F, Hurst J, Woods K, Dunger D, Stanhope R, Forrest S, Robinson IC, Beddington RS 2001 Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet 10:39–45[Abstract/Free Full Text]
19. Flück C, Deladoey J, Rutishauser K, Eble A, Marti U, Wu W, Mullis PE 1998 Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg–>Cys at codon 120 (R120C). J Clin Endocrinol Metab 83:3727–3734[Abstract/Free Full Text]
20. Macchia PE, Lapi P, Krude H, Pirro MT, Missero C, Chiovato L, Souabni A, Baserga M, Tassi V, Pinchera A, Fenzi G, Grüters A, Busslinger M, DiLauro R 1998 PAX8 mutations associated with congenital hypothyroidism caused by thyroid agenesis. Nat Genet 19:83–86[CrossRef][Medline]
21. Mansouri A, Chowdhury K, Gruss P 1998 Follicular cells of the thyroid gland require Pax8 gene function. Nat Genet 19:87–90[CrossRef][Medline]
22. Clifton-Bligh RJ, Wentworth JM, Heinz P, Crisp MS, John R, Lazarus JH, Ludgate M, Chatterjee VK 1998 Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat Genet 19:399–401[CrossRef][Medline]
23. De Felice M, Ovitt C, Biffali E, Rodriguez-Mallon A, Arra C, Anastassiadis K, Macchia PE, Mattei MG, Mariano A, Scholer H, Macchia V, Di Lauro R 1998 A mouse model for hereditary thyroid dysgenesis and cleft palate. Nat Genet 19:395–398[CrossRef][Medline]
24. Damante G, DiLauro R 1994 Thyroid-specific gene expression. Biochim Biophys Acta 1218:255–266[Medline]
25. Vilain C, Rydlewski C, Duprez L, Heinrichs C, Abramowicz M, Malvaux P, Renneborg B, Parma J, Costagliola S, Vassart G 2001 Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8. J Clin Endocrinol Metab 86:234–238[Abstract/Free Full Text]
26. Congdon T, Nguyen LQ, Nogueira CR, Habiby RL, Medeiros-Neto G, Kopp P 2001 A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: evidence for phenotypic variability in mother and child. J Clin Endocrinol Metab 86:3962–3967[Abstract/Free Full Text]
27. Bamforth JS, Hughes IA, Lazarus JH, Weaver CM, Harper PS 1989 Congenital hypothyroidism, spiky hair, and cleft palate. J Med Genet 26:49–51[Abstract]
28. Zannini M, Avantaggiato V, Biffali E, Arnone MI, Sato K, Pischetola M, Taylor BA, Phillips SJ, Simeone A, Di Lauro R 1997 TTF-2, a new forkhead protein, shows a temporal expression in the developing thyroid which is consistent with a role in controlling the onset of differentiation. EMBO J 16:185–197
29. Kimura S, Hara Y, Pineau T, Fernandez-Salguero P, Fox CH, Ward JM, Gonzalez FJ 1996 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 10:60–69[Abstract/Free Full Text]
30. Devriendt K, Vanhole C, Matthis G, De Zegher F 1998 Deletion of thyroid transcription factor-1 gene in an infant with neonatal thyroid dysfunction and respiratory failure. N Engl J Med 338:1317–1318[Free Full Text]
31. Iwatani N, Mabe H, Devriendt K, Kodama M, Miike T 2000 Deletion of NKX2.1 gene encoding thyroid transcription factor-1 in two siblings with hypothyroidism and respiratory failure. J Pediatr 137:272–276[CrossRef][Medline]
32. Pohlenz J, Dumitrescu A, Zundel D, Martine U, Schonberger W, Refetoff S, Hyperthyrotropinemia, respiratory distress and ataxia associated with a mutation in the thyroid transcription factor 1 (TTF-1) gene. Program of the 83rd Annual Meeting of The Endocrine Society, Denver, Colorado, 2001 (Abstract OR43-3)
33. Schuetz BR, Krude H, Biebermann H, von Moers A, Schnabel D, Toennies H, Schwarz S, Neitzel H, Grueters A, Loss of fuction mutations in the NKX2–1 gene define a new syndrome with CNS, thyroid and lung impairment. Program of the 83rd Annual Meeting of The Endocrine Society, Denver, Colorado, 2001 (Abstract OR59-3)
34. Sunthornthepvarakul T, Gottschalk ME, Hayashi Y, Refetoff S 1995 Resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. N Engl J Med 332:155–160[Free Full Text]
35. Abramowicz MJ, Duprez L, Parma J, Vassart G, Heinrichs C 1997 Familial congenital hypotyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland. J Clin Invest 99:3018–3024[Medline]
36. Refetoff S, Sunthornthepvarakul T, Gottschalk M, Hayashi Y 1996 Resistance to thyrotropin and other abnormabilities of the thyrotropin receptor. Recent Prog Hormone Res 51:97–122
37. Kopp P 2001 The TSH receptor and its role in thyroid disease. Cell Mol Life Sci 58:1301–1322[CrossRef][Medline]
38. Stein SA, Oates EL, Hall CR, Grumbles RM, Fernandez LM, Taylor NA, Puett D, Jin S 1994 Identification of a point mutation in the thyrotropin receptor of the hyt/hyt hypothyroid mouse. Mol Endocrinol 8:129–138[Abstract]
39. Weinstein LS, Yu S, Warner DR, Liu J 2001 Endocrine manifestations of stimulatory G protein -subunit mutations and the role of genomic imprinting. Endocr Rev 22:675–705[Abstract/Free Full Text]
40. Xie J, Pannain S, Pohlenz J, Weiss RE, Moltz K, Morlot M, Asteria C, Persani L, Beck-Peccoz P, Parma J, Vassart G, Refetoff S 1997 Resistance to thyrotropin (TSH) in three families is not associated with mutations in the TSH receptor or TSH. J Clin Endocrinol Metab 82:3933–3940[Abstract/Free Full Text]
41. Dai G, Levy O, Carrasco N 1996 Cloning and characterization of the thyroid iodide transporter. Nature 379:458–460[CrossRef][Medline]
42. Smanik P, Liu Q, Furminger T, Ryu K, Xing S, Mazzaferri E, Jhiang S 1996 Cloning of the human sodium iodide symporter. Biochem Biophys Res Commun 226:339–345[CrossRef][Medline]
43. De la Vieja A, Dohan O, Levy O, Carrasco N 2000 Molecular analysis of the sodium/iodide symporter: impact on thyroid and extrathyroid pathophysiology. Physiol Rev 80:1083–1105[Abstract/Free Full Text]
44. Everett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, Adawi F, Hazani E, Nassir E, Baxevanis AD, Sheffield VC, Green ED 1997 Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 17:411–422[CrossRef][Medline]
45. Royaux IE, Suzuki K, Mori A, Katoh R, Everett LA, Kohn LD, Green ED 2000 Pendrin, the protein encoded by the Pendred syndrome gene (PDS), is an apical porter of iodide in the thyroid and is regulated by thyroglobulin in FRTL-5 cells. Endocrinology 141:839–845[Abstract/Free Full Text]
46. Gillam M, Karamanoglu Arseven O, Rutishauser J, Waeber Stephan C, Kopp P, Functional characterization of pendrin and two naturally occurring mutants: evidence for pendrin-mediated iodide efflux. Proc 73rd Annual Meeting of the American Thyroid Association, Washington DC, 2001 (Abstract 196), p 265
47. Gonzalez Trevino O, Karamanoglu Arseven O, Ceballos C, Vives V, Ramirez R, Gomez VV, Medeiros-Neto G, Kopp P 2001 Clinical and molecular analysis of three Mexican families with Pendred’s syndrome. Eur J Endocrinol 144:1–9[Abstract]
48. Gausden E, Armour JA, Coyle B, Coffey R, Hochberg Z, Pembrey M, Britton KE, Grossman A, Reardon W, Trembath R 1996 Thyroid peroxidase: evidence for disease gene exclusion in Pendred’s syndrome. Clin Endocrinol 44:441–446[CrossRef][Medline]
49. Everett LA, Belyantseva IA, Noben-Trauth K, Cantos R, Chen A, Thakkar SI, Hoogstraten-Miller SL, Kachar B, Wu DK, Green ED 2001 Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome. Hum Mol Genet 10:153–161[Abstract/Free Full Text]
50. Abramowicz MJ, Targovnik HM, Varela V, Cochaux P, Krawiec L, Pisarev MA, Propato FVE, Juvenal G, Chester HA, Vassart G 1992 Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter. J Clin Invest 90:1200–1204
51. Pannain S, Weiss RE, Jackson CE, Dian D, Beck JC, Sheffield VC, Cox N, Refetoff S 1999 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[Abstract/Free Full Text]
52. Bakker B, Bikker H, Vulsma T, de Randamie JS, Wiedijk BM, De Vijlder JJ 2000 Two decades of screening for congenital hypothyroidism in The Netherlands: TPO gene mutations in total iodide organification defects (an update). J Clin Endocrinol Metab 85:3708–3712[Abstract/Free Full Text]
53. Dupuy C, Ohayon R, Valent A, Noel-Hudson MS, Deme D, Virion A 1999 Purification of a novel flavoprotein involved in the thyroid NADPH oxidase. Cloning of the porcine and human cDNAs. J Biol Chem 274:37265–37269[Abstract/Free Full Text]
54. De Deken X, Wang D, Many MC, Costagliola S, Libert F, Vassart G, Dumont JE, Miot F 2000 Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family. J Biol Chem 275:23227–23233[Abstract/Free Full Text]
55. Moreno JC, Bikker H, de Randamie J, Wiedijk BM, van Trotsenburg P, Kempers MJ, Vulsma T, de Vijlder JJM, Ris-Stalpers C 2000 Mutations in the ThOX2 gene in patients with congenital hypothyroidism due to iodide organification defects. Endocr J 47(Suppl):107 (Abstract 008)
56. Figueiredo MD, Cardoso LC, Ferreira AC, Campos DV, da Cruz Domingos M, Corbo R, Nasciutti LE, Vaisman M, Carvalho DP 2001 Goiter and hypothyroidism in two siblings due to impaired Ca⁺²/NAD(P)H-dependent H₂O₂-generating activity. J Clin Endocrinol Metab 86:4843–4848[Abstract/Free Full Text]
57. Mendive FM, Rivolta CM, Moya CM, Vassart G, Targovnik HM 2001 Genomic organization of the human thyroglobulin gene: the complete intron-exon structure. Eur J Endocrinol 145:485–496[Abstract]
58. van de Graaf SA, Ris-Stalpers C, Pauws E, Mendive FM, Targovnik HM, de Vijlder JJ 2001 Up to date with human thyroglobulin. J Endocrinol 170:307–321[Abstract]
59. Medeiros-Neto G, Targovnik HM, Vassart G 1993 Defective thyroglobulin synthesis and secretion causing goiter and hypothyroidism. Endocr Rev 14:165–183[Abstract]
60. De Vijlder JJM, Baas F, Koch CAM, Kok K, Gons M 1983 Autosomal dominant inheritance of a thyroglobulin abnormality suggests cooperation of subunits in hormone formation. Ann Endocrinol 44:36
61. Kim PS, Arvan P 1998 Endocrinopathies in the family of endoplasmic reticulum (ER) storage diseases: disorders of protein trafficking and the role of ER molecular chaperones. Endocr Rev 19:173–202[Abstract/Free Full Text]
62. Hishinuma A, Furudate S, Oh-Ishi M, Nagakubo N, Namatame T, Ieiri T 2000 A novel missense mutation (G2320R) in thyroglobulin causes hypothyroidism in rdw rats. Endocrinology 141:4050–4055[Abstract/Free Full Text]
63. Kim PS, Ding M, Menon S, Jung CG, Cheng JM, Miyamoto T, Li B, Furudate S, Agui T 2000 A missense mutation G2320R in the thyroglobulin gene causes non-goitrous congenital primary hypothyroidism in the WIC-rdw rat. Mol Endocrinol 14:1944–1953[Abstract/Free Full Text]
64. Medeiros-Neto G, Stanbury JB 1994 The iodotyrosine deiodinase defect. In: Medeiros-Neto G, Stanbury JB, eds. Inherited disorders of the thyroid system. Boca Raton, FL: CRC Press; 139–159
65. Refetoff S, Weiss RE, Usala SJ 1993 The syndromes of resistance to thyroid hormone. Endocr Rev 14:348–99[CrossRef][Medline]
66. Weiss RE, Refetoff S 2000 Resistance to thyroid hormone. Rev Endocr Metab Disord 1(1–2):97–108
67. Brucker-Davis F, Skarulis MC, Grace MB, Benichou J, Hauser P, Wiggs E, Weintraub BD 1995 Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. Ann Int Med 123:572–583[Abstract/Free Full Text]
68. Takeda K, Sakurai A, DeGroot LJ, Refetoff S 1992 Recessive inheritance of thyroid hormone resistance caused by complete deletion of the protein-coding region of the thyroid hormone receptor-ß gene. J Clin Endocrinol Metab 74:49–55[Abstract]
69. Weiss R, Hayashi Y, Nagaya T, Petty K, Murata Y, Tunca H, Seo H, Refetoff S 1996 Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptor or ß genes may be due to a defective co-factor. J Clin Endocrinol Metab 81:4196–4223[Abstract]
70. Pohlenz J, Weiss RE, Macchia PE, Pannain S, Lau IT, Ho H, Refetoff S 1999 Five new families with resistance to thyroid hormone not caused by mutations in the thyroid hormone receptor ß gene. J Clin Endocrinol Metab 84:3919–3928[Abstract/Free Full Text]
71. Weiss RE, Balzano S, Scherberg NH, Refetoff S 1990 Neonatal detection of generalized resistance to thyroid hormone. JAMA 264:2245–2250[Abstract]
72. Weiss R 1999 Management of patients with resistance to thyroid hormone. Thyroid Today 12:1–11

This article has been cited by other articles:

				J. Mittag, W. Oehr, H. Heuer, T. Hamalainen, B. Brachvogel, E. Poschl, and K. Bauer Expression and thyroid hormone regulation of annexins in the anterior pituitary J. Endocrinol., December 1, 2007; 195(3): 385 - 392. [Abstract] [Full Text] [PDF]

				N. Sasaki, Y. Hosoda, A. Nagata, M. Ding, J.-M. Cheng, T. Miyamoto, S. Okano, A. Asano, I. Miyoshi, and T. Agui A Mutation in Tpst2 Encoding Tyrosylprotein Sulfotransferase Causes Dwarfism Associated with Hypothyroidism Mol. Endocrinol., July 1, 2007; 21(7): 1713 - 1721. [Abstract] [Full Text] [PDF]

				G. Sendin, A. V. Bulankina, D. Riedel, and T. Moser Maturation of Ribbon Synapses in Hair Cells Is Driven by Thyroid Hormone J. Neurosci., March 21, 2007; 27(12): 3163 - 3173. [Abstract] [Full Text] [PDF]

				H. Fagman, J. Liao, J. Westerlund, L. Andersson, B.E. Morrow, and M. Nilsson The 22q11 deletion syndrome candidate gene Tbx1 determines thyroid size and positioning Hum. Mol. Genet., February 1, 2007; 16(3): 276 - 285. [Abstract] [Full Text] [PDF]

				J. Mittag, E. Winterhager, K. Bauer, and R. Grummer Congenital Hypothyroid Female Pax8-Deficient Mice Are Infertile Despite Thyroid Hormone Replacement Therapy Endocrinology, February 1, 2007; 148(2): 719 - 725. [Abstract] [Full Text] [PDF]

				J. Wistuba, J. Mittag, C M. Luetjens, T. G Cooper, C.-H. Yeung, E. Nieschlag, and K. Bauer Male congenital hypothyroid Pax8-/- mice are infertile despite adequate treatment with thyroid hormone J. Endocrinol., January 1, 2007; 192(1): 99 - 109. [Abstract] [Full Text] [PDF]

				American Academy of Pediatrics, S. R. Rose, and the Section on Endocrinology and Committee on, American Thyroid Association, R. S. Brown, and the Public Health Committee, and Lawson Wilkins Pediatric Endocrine Society Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics, June 1, 2006; 117(6): 2290 - 2303. [Abstract] [Full Text] [PDF]

				A. S. Alzahrani, E. Y. Baitei, M. Zou, and Y. Shi Metastatic Follicular Thyroid Carcinoma Arising from Congenital Goiter as a Result of a Novel Splice Donor Site Mutation in the Thyroglobulin Gene J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 740 - 746. [Abstract] [Full Text] [PDF]

				E. Medda, A. Olivieri, M. A. Stazi, M. E Grandolfo, C. Fazzini, M. Baserga, M. Burroni, E. Cacciari, F. Calaciura, A. Cassio, et al. Risk factors for congenital hypothyroidism: results of a population case-control study (1997-2003) Eur. J. Endocrinol., December 1, 2005; 153(6): 765 - 773. [Abstract] [Full Text] [PDF]

				J. Mittag, S. Friedrichsen, H. Heuer, S. Polsfuss, T. J. Visser, and K. Bauer Athyroid Pax8-/- Mice Cannot Be Rescued by the Inactivation of Thyroid Hormone Receptor {alpha}1 Endocrinology, July 1, 2005; 146(7): 3179 - 3184. [Abstract] [Full Text] [PDF]

				L. de Sanctis, A. Corrias, D. Romagnolo, T. DI Palma, A. Biava, G. Borgarello, P. Gianino, L. Silvestro, M. Zannini, and I. Dianzani Familial PAX8 Small Deletion (c.989_992delACCC) Associated with Extreme Phenotype Variability J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5669 - 5674. [Abstract] [Full Text] [PDF]

				H. Fagman, M. Grande, A. Gritli-Linde, and M. Nilsson Genetic Deletion of Sonic Hedgehog Causes Hemiagenesis and Ectopic Development of the Thyroid in Mouse Am. J. Pathol., May 1, 2004; 164(5): 1865 - 1872. [Abstract] [Full Text] [PDF]

				S. Friedrichsen, S. Christ, H. Heuer, M. K. H. Schafer, A. F. Parlow, T. J. Visser, and K. Bauer Expression of Pituitary Hormones in the Pax8-/- Mouse Model of Congenital Hypothyroidism Endocrinology, March 1, 2004; 145(3): 1276 - 1283. [Abstract] [Full Text] [PDF]

				J. K. Inlow and L. L. Restifo Molecular and Comparative Genetics of Mental Retardation Genetics, February 1, 2004; 166(2): 835 - 881. [Abstract] [Full Text] [PDF]

				P. Caron, C. M. Moya, D. Malet, V. J. Gutnisky, B. Chabardes, C. M. Rivolta, and H. M. Targovnik Compound Heterozygous Mutations in the Thyroglobulin Gene (1143delC and 6725G->A [R2223H]) Resulting in Fetal Goitrous Hypothyroidism J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3546 - 3553. [Abstract] [Full Text] [PDF]

				S. Friedrichsen, S. Christ, H. Heuer, M. K. H. Schafer, A. Mansouri, K. Bauer, and T. J. Visser Regulation of Iodothyronine Deiodinases in the Pax8-/- Mouse Model of Congenital Hypothyroidism Endocrinology, March 1, 2003; 144(3): 777 - 784. [Abstract] [Full Text] [PDF]

				T. C. Vieira, M. R. Dias da Silva, J. M. Cerutti, E. Brunner, M. Borges, L. T. Arnaldi, P. Kopp, and J. Abucham Familial Combined Pituitary Hormone Deficiency due to a Novel Mutation R99Q in the Hot Spot Region of Prophet of Pit-1 Presenting as Constitutional Growth Delay J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 38 - 44. [Abstract] [Full Text] [PDF]

				R. S. Brown and L. A. Demmer The Etiology of Thyroid Dysgenesis--Still an Enigma after All These Years J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4069 - 4071. [Full Text] [PDF]

This Article