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A Population-Based Study on the Frequency of Additional Congenital Malformations in Infants with Congenital Hypothyroidism: Data from the Italian Registry for Congenital Hypothyroidism (1991–1998)

National Institute of Health (A.O., M.A.S., C.F., E.M., S.D.A., M.E.G., D.T., V.C., M.S.), Catholic University of Sacred Heart (P.M.), and Institute of Social Medicine (A.S.), 00161 Rome, Italy

Address all correspondence and requests for reprints to: Dr. Antonella Olivieri, Laboratory Metabolismo e Biochimica Patologica, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy. E-mail: olivieri{at}iss.it

Abstract

In the last decade a high frequency of other congenital anomalies has been reported in infants with congenital hypothyroidism (CH) detected by neonatal screening. In the present study the occurrence of additional congenital malformations (CM) in the population of CH infants detected in Italy between 1991 and 1998 (n = 1420) was investigated. In Italy all of the centers in charge of screening, treatment, and follow-up of CH adhere to the Italian National Registry of infants with CH.

In this study a high prevalence of additional CM (8.4%), more than 4-fold higher than that reported in the Italian population (1–2%), was found in the population of CH infants. Cardiac anomalies represented the most frequent malformations associated with CH, with a prevalence of 5.5%. However, a significant association between CH and anomalies of nervous system, eyes, and multiple CM was also observed. In conclusion, the significantly higher frequency of extrathyroidal congenital malformations reported in the CH infants than in the general population represents a further argument supporting the role of a genetic component in the etiology of CH. Investigations of the molecular mechanisms underlying developmental events of formation of thyroid and other organs represent critical steps in the knowledge of CH etiology.

CONGENITAL HYPOTHYROIDISM (CH) is one of the most common preventable causes of mental retardation. Because few signs or symptoms are present in the neonatal period, routine screening is the only means of detection. The aim of the screening program is the prevention of mental retardation by early diagnosis and therapy (1, 2, 3, 4). The neonatal screening program for CH started in Italy in 1977 and then progressively developed covering the entire neonatal population. The Italian National Population-Based Registry of Infants with CH (INRCH) was established in Italy in 1987 as a program of the Health Ministry and is coordinated by the National Institute of Health (5). In Italy the incidence of CH is about 1 in 3000 live births, an incidence slightly higher than that observed in other countries where iodine prophylaxis is carried out (6).

Most permanent cases of CH (80–85%) are due to thyroid dysgenesis resulting from alterations in thyroid development during embryogenesis. Recently several cases of thyroid dysgenesis have been shown to be associated with mutations in genes (TTF1, TTF2, PAX8, and TSHR) involved in the development of thyroid follicular cells (7, 8). However, thyroid organogenesis is a complex process, and other genes are expressed during thyroid gland formation. In the last decade a high frequency of other congenital defects, mostly cardiac, has been reported in infants with CH detected by neonatal screening (9, 10, 11, 12, 13). It is becoming clearer that studying additional congenital malformations (CM) in CH infants has important implications for understanding the etiology of CH.

In the present study the occurrence of additional CM in the population of CH infants detected in Italy between 1991 and 1998 was investigated. The aims of the present study were 1) to estimate the prevalence of additional CM in the Italian population of infants with CH recorded in the INRCH, 2) to compare the frequency of additional CM in the CH population with that observed in the general population, 3) to verify whether the occurrence of additional CM may affect the effectiveness of the neonatal thyroid screening program in Italy.

Subjects and Methods

In Italy neonatal screening for CH is performed by 26 regional or interregional centers. Positive results of screening tests are confirmed by definitive tests of thyroid function on serum. Confirmational tests include TSH, T₄, and/or free T₄. Infants with confirmed primary CH were referred to the follow-up centers of their own region for starting replacement therapy (5). At present in Italy replacement therapy is started at median age of 19 d.

Babies with transient hyperthyreotropinemia on the basis of spontaneous normalization of TSH between screening and diagnosis were not recorded in the Registry. According to international guide lines (14, 15), when the definitive diagnosis of hypothyroidism is not established in the neonatal period and a suspicion of transient primary hypothyroidism (TH) is present, reevaluation of CH diagnosis is performed at the age of 2–3 yr. At that time, after a 4-wk withdrawal period of L-T₄ treatment, T₄, free T₄, and TSH levels are measured, and ultrasound imaging, scintigraphy, and clinical evaluation are performed to establish the definitive diagnosis. In this study infants with ascertained TH were considered separately.

The birth registration form filled in at diagnosis includes anonymous data concerning CH infants (5). Since 1991 the Register has been requesting specific data on the occurrence of congenital anomalies (detected during neonatal period) other than those of the thyroid gland by using a specific reporting form.

The written descriptions of all congenital malformations reported in the Registry were reviewed in the original form by the Director of the International Center for Birth Defects (http://www.icbd.org), which has been established to coordinate the activities of the International Clearinghouse for Birth Defects Monitoring System (16). Mild and minor malformations, such as cryptorchidism, patent foramen ovalis and patent ductus arteriosus in low birth weight infants, and congenital hip dysplasia, were not considered. All other anomalies were classified as major malformations and coded with the International Classification of Diseases, ninth revision. All of the reported forms of infants with two or more malformations were reviewed once again to detect similarities in their association pattern. All major malformations were counted regardless of whether they were isolated, and their birth prevalence per 100 was calculated.

Comparison with other registries

As the infants of general population are not so deeply examined as infants with CH, the possibility of an underestimated birth prevalence of CM in the general population may not be excluded. For this reason the available data of many registries participating in the International Clearinghouse for Birth Defects Monitoring System were screened, and those with the highest prevalence figures, including terminations and based on a large number of births, were chosen for comparing data.

The main categories of congenital malformations observed in the population of CH infants were compared with data from Congenital Malformation Registry of Victoria State-Australia. This Registry was chosen after screening of a large number of congenital malformation registries because it showed the highest figure available (3.1/100 births) computed on a large number of births (>750,000) in a 12-yr period without variations over the years. It includes terminations of pregnancy and tabulates data of anomalies.

Data concerning the frequency of cardiac malformations in the CH population were compared with data from eight different registries (Florence, Baltimore, Tyrol, Strasbourg, Dallas, Indagine Policentrica Italiana Malformazioni Congenite, and Australia) (17, 18, 19, 20, 21, 22). In the Florence and Baltimore registries a 1-yr follow-up of the recruited infants was obtained. For each cardiac anomaly the highest figure reported in one of these eight registries was used as the expected value to compare with that observed in the Italian population of CH infants.

Statistical analysis

A t test was used to evaluate differences between mean values of variables. The log-normal transformation was used for data that was not normally distributed. Differences in the proportion of CH infants with and without major CM were examined statistically by ² test. Observed/expected (O/E) ratios and 95% confidence intervals (CI) were calculated according to the Poisson distribution for rare events.

Results

Between 1991 and 1998, 1420 CH infants were identified among 4,284,981 live births screened in Italy in that period. One hundred and fifty-four of the 1420 CH infants were reevaluated at the age of 2–3 yr because of the high suspicion of TH. The diagnosis of TH was established in 33 infants (18 males and 15 females), resulting in an incidence of permanent CH of 1:3089 (n = 1387).

Infants with confirmed CH

Among the 1387 infants with CH, 15 babies with Down syndrome (1.1%) were excluded from the analysis because of the known association of this syndrome with transient thyroid dysfunction (23). One hundred and sixty-nine of the remaining 1372 CH infants had additional birth defects. Among these babies, 115 had major anomalies, with a prevalence of 8.4%.

Thyroid scan with ⁹⁹Tc was performed before the onset of therapy in 57.2% of infants with isolated CH and in 58.2% of infants with major CM (Fig. 1). No significant differences were observed in the frequency of normal gland, hypoplasia, hyperplasia, and agenesis between the groups. As a higher prevalence of CM has been reported in infants with TH than in those with permanent CH (24), in our study the prevalence of major CM was also estimated in a group of CH infants with thyroid ultrascan diagnosis indicating permanent CH (ectopy, hypoplastic gland, and agenesis confirmed by ultrasound findings). This was to avoid a possible overestimation of additional CM due to inclusion in the study of TH infants not yet reevaluated. Thirty-four of the 490 CH infants with diagnosis of permanent CH had major CM with a prevalence (6.9%) not significantly different from that found in the remaining population of CH infants (9.2%, 81 of 882).

View larger version (25K): [in this window] [in a new window]   Figure 1. Scintigraphic diagnosis of infants with CH.

View larger version (15K): [in this window] [in a new window]   Figure 2. Distribution of the main categories of major CM observed in CH infants.

Table 1 presents O/E ratios for the main categories of major CM. The expected values were obtained from the Victoria Congenital Malformation Registry (1983–1994). The O/E ratio analysis showed that anomalies regarding nervous system (O/E ratio, 2.7; 95% CI, 1.4–4.7), eyes (O/E ratio, 5.5; 95% CI, 2.0–11.9), heart (O/E ratio, 5.5; 95% CI, 4.3–7.0), and multiple (3+) congenital anomalies (O/E ratio, 7.2; 95% CI, 2.2–20.6) were significantly more frequent in the CH infants than in the reference population.

The O/E ratios for cardiac defects are shown in Table 2. For each cardiac anomaly the highest figure reported in one of these eight considered registries was used as the expected value. The O/E ratio analysis showed that tetralogy of Fallot (O/E ratio, 8.6; 95% CI, 3.1–18.7), ASD-ostium II (O/E ratio, 10.6; 95% CI, 6.4–16.5), and pulmonary stenosis (O/E ratio, 7.8; 95% CI, 3.1–16.0) are significantly more frequent than those observed in the reference population.

Mean levels of T₄ and TSH at screening and confirmation and some neonatal features observed in the infants with isolated CH were compared with those of infants with major additional CM. Significantly lower serum T₄ levels at screening were observed in the group with major CM than in the infants with isolated CH (3.1 ± 2.4 vs. 4.0 ± 2.8 µg/dl; P = 0.04). However, no difference between groups was found at confirmation of the diagnosis. Birth weight was significantly lower in CH infants with major CM than in those with isolated CH (3027 ± 732 vs. 3225 ± 697 g; P = 0.01). Comparison of mean values of gestational age and female/male ratio did not show any significant difference between the groups. Also, the frequency of twins was similar in the two groups: 3.0% in CH infants with major CM and 3.6% in those with isolated CH.

Reevaluated infants with TH

Five (3 females and 2 males) of the 33 infants with ascertained TH had additional congenital anomalies. Two of them (6.1%) had Down syndrome with cardiac septal defects. In the 3 remaining TH infants the following anomalies were observed: ventricular septal defect, persistent fetal circulation, and clubfoot. The prevalence of additional CM in the TH infants, with exclusion of the 2 babies with Down syndrome, was not significantly different from that found in the population of infants with confirmed CH (9.7% and 8.4%, respectively).

Effects on effectiveness of the Italian screening program

Although a significant delay in collection of screening specimens was observed in CH infants with major CM (age at screening, 6.6 ± 6.7 vs. 4.7 ± 3.5 d; P = 0.01), no significant differences between groups were found in the mean age at the start of therapy.

Discussion

In this study a high prevalence of additional CM (8.4%), more than 4-fold higher than that reported in the Italian population, was found in the population of CH infants diagnosed in Italy between 1991 and 1998 and recorded by the INRCH. This finding confirms the high prevalence of additional CM previously reported in other series of infants with CH (9, 10, 11, 12, 13). The wide variation in the frequencies of additional CM reported in CH infants (range, 7.3–24.0%) can be due to the size of the sample, to the criteria of inclusion of cases in the study, and to the different geographical location of the considered population. Although there are no doubts on the prevailing view that CH is associated with other malformations, it has been reported that a high frequency of additional CM is more often present in infants with transiently elevated TSH than in those with definitive CH (24). In the our study the population of CH infants included neither babies with transient hyperthyreotropinemia showing a spontaneous normalization of TSH between screening and diagnosis nor TH infants identified after reevaluation of the diagnosis. Moreover, the estimated prevalence of major CM in this CH population was not significantly affected by the possible presence of not yet reevaluated children with TH. In fact, the prevalence of major CM observed in the subgroup of the 490 CH infants with scintigraphic diagnosis indicating permanent CH was not significantly different from that found in the remaining population of CH infants (6.9% and 9.2%, respectively).

The question of whether additional CM may influence the effectiveness of the Italian thyroid screening program has been also considered. This study showed that no delay at the start of therapy is observed in the group of CH infants with additional CM compared with the infants with isolated CH.

Several studies have supported that genetic factors may be involved in the pathogenesis of CH. It has been reported how mutations in the genes encoding transcription factors (TTF1, TTF2, and PAX8) or the TSH receptor cause thyroid dysgenesis in humans or in mouse models (6, 7). Moreover, a familial clustering, including athyreosis and ectopic thyroid gland, has been recently reported (27). This finding strongly suggests the potential involvement of genetic factors, potentially including other genes that are as yet unknown. Again, the significantly higher frequency of extrathyroidal congenital malformations reported in the CH infants than in the general population represents a further argument supporting the role of a genetic component in the etiology of CH. Our results obtained from a large population of CH infants confirmed a strong association between CH and additional CM, mostly for multiple anomalies and for anomalies regarding nervous system, eyes, and heart. The high frequency of multiple congenital anomalies found in the population of CH infants strongly suggests a very early impairment in the first stages of embryo development with a consequent involvement of different organs and structures. The hypothesis that hypothyroidism per se (especially in the first 10 wk of fetal life) may play a role in the occurrence of CM cannot be excluded. This hypothesis is also supported by the fact that CH babies with CM showed significantly lower T₄ levels at screening than babies with isolated CH. However, the significant association between CH and anomalies of nervous system, eyes, and heart (representing precocious structures in the developing embryo) fits with results obtained in studies conducted in experimental models. In these studies anomalies occurring in organs that are dependent on neural crest cells for their development were hypothesized to result from a disturbance of the proliferation and migration of the neural crest cells in the early phases of embryo development (28, 29, 30, 31). These cells represent a migratory cell population derived from the dorsal neural tube that contributes to a wide variety of tissues throughout the embryo. Studies of avian and mouse embryos demonstrated that a neural crest subpopulation, termed cardiac neural crest, plays a vital role in the normal heart morphogenesis and contributes cells to the aortic arches, thymus, thyroid, and parathyroids (31, 32). Ablation studies in the chick have also demonstrated the occurrence of cardiac outflow tract defects frequently in association with defective or absent thymus, thyroid, and parathyroids (28, 33).

In this study cardiac anomalies were the most frequent CM observed in the CH infants. The O/E analysis also showed a significant association of CH with ASD-ostium II, tetralogy of Fallot, and pulmonary stenosis. It is important to consider the fact that embryonic thyroid development is closely associated with the developing heart. The thyroid is pulled to its position near the base of the neck as a consequence of the continuing descent of the heart during the early stages of thyroid formation (34). It has been reported that mutations in developmental control genes are associated with some cardiac congenital malformations (35). Many point mutations have been identified in NKX2.5 transcription factor in families with atrial septal defects (36). Sporadic mutations of NKX2.5 have also been found in patients with tetralogy of Fallot (37). Isolated pulmonary stenosis and tetralogy of Fallot have been associated with Jagged-1 mutations (38). Again, recent studies conducted in experimental models have implicated the homeobox gene Hex in the development of the cardiovascular system and the thyroid gland (39, 40). In the light of this evidence, investigations of the molecular mechanisms underlying developmental events of heart and thyroid formation and understanding how perturbations of possible common developmental control genes may result in thyroid dysgenesis and in different forms of congenital heart disease represent critical steps in the knowledge of CH etiology.

In conclusion, many pathogenic mechanisms may be involved in the increasing frequency of additional congenital anomalies in infants with CH. Elucidation of genetic-environmental networks and mechanisms underlying the development of thyroid and other organs opens up the possibility of understanding the etiology of CH and provides hope that at least some types of thyroid dysgenesis may be prevented by modulating these cofactors. In this view epidemiological studies are relevant because they can promote and orient future molecular studies to more precise targets.

Acknowledgments

The skillful technical assistance of Mrs. F. Latini is gratefully acknowledged.

Footnotes

¹ R. Altamura (Brindisi), U. Angeloni (Rome), R. Antonetti (Foggia), I. Antonozzi (Rome), M. Baserga (Catanzaro), R. Berardi (Siena), S. Bernasconi (Parma), G. Bona (Novara), M. Burroni, E. Cacciari (Bologna), R. Caldarera (Messina), A. Cassio (Bologna), L. Cavallo (Bari), L. Chiovato (Pisa), G. Chiumello (Milano), B. Ciannamea (Lecce), A. Cohen (Savona), G. V. Coppa (Ancona), C. Corbetta (Milano), R. Cordova (Potenza), P. Costa (Rome), F. Dammacco (Bari), F. De Luca (Messina), C. De Santis (Torino), C. Del Carpio (Palermo), S. Di Maio (Napoli), G. F. Fenzi (Napoli), R. Gastaldi (Genova), R. Gaudio (Taranto), G. Giovannelli (Parma), D. Gullo (Catania), L. Lasciarrea (Bari), A. Lelli (Rome), A. Liotta (Palermo), D. Lojodice (Napoli), R. Lorini (Genova), F. Monaco (Chieti), L. Moschini (Rome), G. C. Mussa (Torino), N. Oggiano (Ancona), S. Pagliardini (Torino), L. Palillo (Palermo), G. Parlato (Catanzaro), E. Pasquini (Firenze), S. Piazzi (Bologna), A. Pignero (Napoli), A. Pinchera (Pisa), C. Pintor (Cagliari), R. Puggioni (Cagliari), A. Rizzo (Lecce), C. Romano (Genova), G. Saggese (Pisa), D. Sala (Napoli), C. Salerno (Napoli), R. Salti (Firenze), L. Sava (Catania), V. Stoppioni (Fano), F. Tancredi (Napoli), L. Tatò (Verona), R. Vigneri (Catania), N. Vizzini (Caltanissetta), C. Volta (Parma), G. Weber (Milano), and E. Zammarchi (Firenze).

Abbreviations: ASD, Atrial septal defects; CH, congenital hypothyroidism; CI, confidence interval; CM, congenital malformations; INRCH, Italian National Registry of infants with congenital hypothyroidism; O/E ratio, observed/expected ratio; TH, transient primary hypothyroidism.

This work was supported by Health Ministry Project 2000, N°0AH/F Molecular Basis of Congenital Hypothyroidism.

Received August 7, 2001.

Accepted November 5, 2001.

References

1. Klein AH, Meltzer S, Kenny FM 1972 Improved prognosis in congenital hypothyroidism treated before age three months. J Pediatr 81:912–915[CrossRef][Medline]
2. New England Congenital Hypothyroidism Collaborative 1984 Characteristics of infantile hypothyroidism discovered on neonatal screening. J Pediatr 104:539–544[Medline]
3. Rovet J, Ehrich R, Sorbara D 1987 Intellectual outcome in children with fetal hypothyroidism. J Pediatr 110:700–704[CrossRef][Medline]
4. Heyerdahl S, Kase BF, Lie SO 1991 Intellectual development in children with congenital hypothyroidism in relation to recommended thyroxine treatment. J Pediatr 118:850–857[CrossRef][Medline]
5. Sorcini M, Balestrazzi P, Grandolfo ME, Carta S, Giovannelli G 1993 The National Register of infants with congenital hypothyroidism detected by neonatal screening in Italy. J Endocrinol Invest 16:573–577[Medline]
6. Working Group on Congenital Hypothyroidism of European Society for Pediatric Endocrinology 1990 Epidemiological inquiry on congenital hypothyroidism in Europe, 1985–1988. Horm Res 34:1–3[Medline]
7. Macchia PE, De Felice M, Di Lauro R 1999 Molecular genetics of congenital hypothyroidism. Curr Opin Genet Dev 9:289–294[CrossRef][Medline]
8. Macchia PE 2000 Recent advances in understanding the molecular basis of primary congenital hypothyroidism. Mol Med Today 6:36–42[CrossRef][Medline]
9. Lazarus JH, Hughes IA 1988 Congenital abnormalities and congenital hypothyroidism. Lancet 2:52
10. Siebner R, Merlob P, Kaiserman I, Sack J 1992 Congenital anomalies concomitant with persistent primary congenital hypothyroidism. Am J Med Gen 44:57–60[CrossRef][Medline]
11. Cassio A, Tatò L, Colli C, Spolettini E, Costantini E, Cacciari E 1994 Incidence of congenital malformations in congenital hypothyroidism. Screening 3:125–130[CrossRef]
12. Roberts HE, Moore CA, Fernhoff PM, Brown AL, Khoury MJ 1997 Population study of congenital hypothyroidism and associated birth defects, Atlanta, 1979–1992. Am J Med Gen 71:29–32[CrossRef][Medline]
13. Al-Jurayyan NA, Al-Herbish AS, El-Desouki MI, Al-Nuaim AA, Abo-Bakr AM, Al-Husain MA 1997 Congenital anomalies in infants with congenital hypothyroidism: is it a coincidental or an associated finding? Hum Hered 47:33–37[CrossRef][Medline]
14. ESPE Working Group an Congenital Hypothyroidism 1993 Guidelines for neonatal screening programs for congenital hypothyroidism. Eur J Pediatr 152:974–975[CrossRef][Medline]
15. American Academy of Pediatrics 1993 Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics 91:1203–1209[Abstract/Free Full Text]
16. International Clearinghouse for Birth Defects 2000 Monitoring system annual report. Rome: International Center for Birth Defects
17. Manetti A, Pollini I, Cecchi F, De Simone L, Cianciulli D, Carbone C, Romenelli A, Bianchi F, Dolara A 1993 The epidemiology of cardiovascular malformations. III. The prevalence and follow-up of 46,895 live births at the Careggi Maternity Hospital, Florence, in 1975–1984. G Ital Cardiol 23:145–152[Medline]
18. Ferencz C, Rubin DJ, Loffredo AC, Magee AC 1993 Epidemiology of congenital heart disease. The Baltimore-Washington Infant Study 1981–1989. Perspectives in pediatric cardiology, vol 4. New York: Mount Kisco Futura
19. Fischer H, Sonnweber N, Sailer M, Fink C, Trawoger R, Hammerer I 1991 Incidence of congenital heart disease in Tyrol, Austria 1979–1983. Pediatr Pathol 26:57–60
20. Stoll C, Alembik Y, Roth MP, Dott B, De Geeter B 1989 Risk factors in congenital heart disease. Eur J Epidemiol 5:382–391[CrossRef][Medline]
21. Fixler DE, Pastor P, Chamberlin M, Sigman E, Eifler CW 1990 Trends in congenital heart disease in Dallas County births. 1971–1984. Circulation 81:137–142[Medline]
22. Kidd SA, Lancaster PAL, McCredie RM 1993 The incidence of congenital heart defects in the 1^st year of life. J Paediatr Child Health 29:344–349[Medline]
23. Fort P, Lifshitz F, Bellisario R, Davis J, Lanes R, Pugliese M, Richman R, Post EM, David R 1984 Abnomalities of thyroid function in infants with Down’s syndrome. J Pediatr 104:545–549[Medline]
24. Oakley GA, Muir T, Ray M, Girdwood RW, Kennedy R, Donaldson MD 1998 Increased incidence of congenital malformations in children with transient thyroid stimulating hormone elevation on neonatal screening. J Pediatr 132:726–730[CrossRef][Medline]
25. Marino B, Dallapiccola B, Mastroiacovo P 1995 Cardiopatie congenite e sindromi genetiche. Milan: McGraw-Hill Libri Italia; 13–27
26. Devos H, Rodd C, Gagné 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]
27. 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]
28. Kirby ML, Waldo KL 1990 Role of neural crest in congenital heart disease. Circulation 82:332–340[Medline]
29. Kirby ML 1993 Cellular and molecular contributions of the cardiac neural crest to cardiovascular development. Trends Cardiovasc Med 3:18–23
30. Siman CM, Gittenberger-De Groot AC, Wisse B, Eriksson UJ 2000 Malformations in offspring of diabetic rats: morphometric analysis of neural crest-derived organs and effects of maternal vitamin E treatment. Teratology 61:355–367[CrossRef][Medline]
31. Hall BK, Horstadius S 1988 The neural crest. New York: Oxford University Press
32. Franz T 1989 Persistent truncus arteriosus in the Splotch mutant mouse. Anat Embryol 180:457-464[CrossRef][Medline]
33. Bockman DE, Kirby ML 1984 Dependence of thymus development on derivatives of the neural crest. Science 223:498–500[Abstract/Free Full Text]
34. Pintar JE 1996 Normal development of the hypothalamic-pituitary-thyroid axis. In: Braverman LE, Utiger RD, eds. The thyroid. Philadelphia: Lippincott-Raven
35. Srivastava D, Olson EN 2000 A genetic blueprint for cardiac development. Nature 407:221–226[CrossRef][Medline]
36. Schott JJ, Benson DW, Basson CT, W, Silberbach GM, Moak JP, Maron BJ, Seidman CE, Seidman JG 1998 Congenital heart disease caused by mutations in the transcription factor NKX2.5. Science 281:108–111[Abstract/Free Full Text]
37. Benson DW, Silberbach GM, Kavanaugh-McHugh A, Cottrill C, Zhang Y, Riggs S, Smalls O, Johnson MC, Watson MS, Seidman JG, Seidman CE, Plowden J, Kugler JD 1999 Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. J Clin Invest 104:1567–1573[Medline]
38. Krantz ID, Smith R, Colliton RP, Tinkel H, Zackai EH, Piccoli DA, Goldmuntz E, Spinner NB 1999 Jagged 1 mutations in patients ascertained with isolated congenital heart defects. Am J Hum Genet 84:56–60
39. Yatskievych TA, Pascoe S, Antin PB 1999 Expression of the homeobox gene Hex during early stages of chick embryo development. Mech Dev 80:107–109[CrossRef][Medline]
40. Thomas PQ, Brown A, Bendington RSP 1998 Hex: a homeobox gene revealing peri-implantation asymmetry in the mouse embryo and an early transient marker of endothelial cell precursor. Development 125:85–94[Abstract]

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