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Higher incidence of thyroid agenesis in Mexican newborns with congenital hypothyroidism associated with birth defects
Early Human Development 88 (2012) 61–64
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Higher incidence of thyroid agenesis in Mexican newborns with congenital hypothyroidism associated with birth defects Susana Monroy-Santoyo a, Isabel Ibarra-González b, Cynthia Fernández-Lainez a, Sydney Greenawalt-Rodríguez a, Jorge Chacón-Rey a, Raúl Calzada-León a, Marcela Vela-Amieva a,⁎ a b
Instituto Nacional de Pediatría, Secretaría de Salud, Mexico Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, UNAM, Mexico
a r t i c l e
i n f o
Article history: Received 18 May 2011 Received in revised form 5 July 2011 Accepted 6 July 2011 Keywords: Congenital hypothyroidism Birth defects Newborn screening Congenital malformations Thyroid agenesis
a b s t r a c t Background: Congenital hypothyroidism (CH) is the most common endocrine system disorder in newborns. Ectopic thyroid and agenesis are the most frequent thyroid structural malformations. Several reports have shown that CH is associated with birth defects (BD) ranging from congenital heart disease to ocular and gastrointestinal anomalies. Aims: We investigated how many and what types of BD were associated with CH in Mexican children. Study design: Cross-sectional study conducted in patients with confirmed CH. Setting: Highly specialized government pediatric center in Mexico City. Subjects: We included 212 patients with permanent CH identified by newborn screening. Results: We found that 24% of patients with CH also had BD, and that there was a higher prevalence of thyroid agenesis in the group of patients with CH associated with BD (CH + BD) versus the isolated CH group (p = 0.007). There were more females than males in both groups. The most common BD were congenital heart diseases, especially those of the atrial septum, followed by patent ductus arteriosus, found as a single malformation or as part of a complex congenital heart disease. In this study, we found Hirschsprung disease, Beckwith–Wiedemann syndrome, Pierre Robin sequence, Albright's osteodystrophy, VATER association, and frontonasal dysplasia associated with CH. Conclusions: In this study population, there was a high prevalence of BD in patients with permanent CH. Thyroid agenesis was the main etiological cause of CH in patients with associated congenital malformations. The high prevalence of CH + BD underlines the need for a comprehensive clinical diagnostic approach of the patients with CH. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Birth defects (BD) occur in 3–4% of newborns (NB) worldwide [1]. Congenital hypothyroidism (CH) is the most common disorder of the endocrine system in newborns; it affects 3 in 10,000 NB (1:2000 to 1:4000 NB) [2] and is more common in females [3]. The global prevalence of CH varies widely among biogeographical areas and populations, and there may be associated environmental (nutritional) and genetic factors [4]. In the majority of children with CH the thyroid gland shows structural malformations called thyroid dysgenesis, which includes defects in the differentiation or survival of thyroid follicular cells, which leads to thyroid agenesis or athyreosis in approximately 20% cases of patients with of thyroid dysgenesis, or in the downward migration of the median thyroid anlage during embryonic development, resulting in ⁎ Corresponding author. E-mail address: [email protected] (M. Vela-Amieva). 0378-3782/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2011.07.009
ectopic thyroid in the remaining 80% of patients with thyroid dysgenesis [5]. Several reports have shown a high frequency of CH associated with BD in different populations, ranging from congenital heart disease to ocular and gastrointestinal anomalies [6–8]. Recent studies have proposed that babies with CH should be thoroughly examined to detect BD using techniques such as echocardiography and renal ultrasonography [9,10]. The association between CH + BD is not fully understood, but there may be a genetic component that interferes with early morphogenesis, causing derangement in several organs and systems [11,12]. It is known that CH is more common in Hispanic populations [13]; there are documented rates of eight cases per 10,000 NB in some geographic areas of Mexico [14]. However, there are no data available regarding the association between CH + BD in the Mexican population. Thus, our objective was to investigate how many and what kinds of BD were associated with CH in a highly specialized pediatric hospital setting.
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2. Materials and methods This cross-sectional study was conducted in a convenience sample comprising patients with CH at the National Institute of Pediatrics in Mexico City. After approval by the Institute's investigation and ethics committees, we included the files of Mexican patients diagnosed with CH by newborn screening (NBS) based on thyrotropin levels N10 IU/mL (thyrotropin levels were measured with an enzyme-linked immunosorbent assay) [14]. The CH diagnosis was confirmed by thyroid function tests: thyrotropin (N4 IU/mL), low total triiodothyronine (b72 ng/dL), and low free thyroxine (b0.8 ng/dL). 99mTC radionuclide thyroid scintigraphy was performed before the onset of therapy. An informed consent was signed by the parents of the infants. The recorded CH clinical data included: umbilical hernia, jaundice, dry skin, constipation, characteristic facies, hoarse cry, large posterior fontanel, edema, macroglossia, somnolence, hypotonia, slow feeding, hypothermia, respiratory distress, congenital hip dislocation, heart murmur, and perioral cyanosis. Patients with Down syndrome were excluded from the study, because of the known association of the syndrome with thyroid dysfunction. Preterm newborns with patent ductus arteriosus (PDA) as the only BD present were also excluded, because of this condition's association with premature birth. The patients were clinically examined and classified as follows: [1] Isolated CH (with no BD associated), [2] CH with a single BD, [3] CH with two or more BD, and [4] CH with syndromes or associated diseases. A comparison of proportions to determine statistical significance was performed with MedCalc software version 7.3.0.1 and Stata data analysis and statistical software. A p value of b0.05 was considered to be significant. 3. Results We analyzed the cases of 212 CH infants who were born over a 6-year period (2000–2006). The studied population had the following demographic data: mean maternal age, 26 years (14–44 years); mean number of gestations, 2 [1–8]; and mean gestational age, 39 weeks (29–42 years). Eighty-one patients (44%) were delivered by cesarean section, and 103 (56%) were delivered by uncomplicated vaginal birth. The distribution by sex was 135 (73%) females and 49 (27%) males. The mean birth weight and height were 3183 g (range 1000– 5000 g) and 49.6 cm (range 40–56 cm), respectively. CH in all of the cases was identified by NBS; however, the infants' age upon referral to our center was between 5 days and 4 months. The most prominent clinical data were: umbilical hernia (78%), hoarse cry (67%), jaundice (65%), constipation (63%), macroglossia (56%), hypoactivity (49%), and dry skin (46%). Of the 212 patients, there were 106 patients with ectopic thyroid (77 females and 29 males), 76 with agenesis (57 females and 19 males), two with goiter or dyshormonogenesis (one female and one male), and 28 without feasible etiological diagnoses resulting from radionuclide thyroid scintigraphy (15 females and 13 males). The medians and ranges of TSH and free T4 at diagnosis for these etiological groups are shown in Table 1. The comparison of proportions of both TSH and free T4 among the different etiological groups was statistically significant (p = 0.007 and p = 0.006, respectively) when the group without feasible etiological diagnoses was compared to the other
groups. In this cohort, 160 patients had isolated CH and 52 patients (24%) presented one or more associated BD. Of the CH + BD patients, 33 had only one BD, 12 had two or more BD, and seven had a syndrome or associated disease. Fig. 1 shows the patients classified into two groups: isolated CH and CH + BD. The CH etiology and sex of the patients is also listed in Fig. 1. We found a higher prevalence of thyroid agenesis in the CH + BD group versus the isolated CH group; this comparison was statistically significant (p = 0.007). There were more females than males in all of the groups. Table 2 describes the patients' BD according to their number, syndrome or disease, and affected organ or system. 4. Discussion Our results revealed a high frequency of BD associated with CH (24%). The frequencies found by us and by Roberts et al. [6] are higher than those found by other authors [15–17]. The prevalence of the different forms of thyroid dysgenesis varies depending on the diagnostic tool used for thyroid imaging [18]; however, in our center, the same diagnostic modality ( 99mTc scintigraphy) was performed with all of the participants. The most noticeable finding of our study was the higher prevalence of agenesis as the main etiological cause of CH in the CH + BD group in contrast to the isolated CH group, in which thyroid ectopia was the most common cause. As mentioned previously, thyroid ectopia is the most common cause of isolated CH [18,19]; however, to our knowledge, this is the first study in a Mexican population to find a difference in CH etiology in patients with CH + BD. Interestingly, in this cohort the number of patients with goiter/ dyshormonogenesis was low. The statistically significant difference in THS and free T4 values found between the group of patients without feasible etiological diagnosis and the others, suggests that in the former the goiter/dyshormonogenesis cases may be included as thyroid enlargement is not often detected clinically at birth. There was no difference in the birth weight and height of the newborns in our study compared to the data established by the Official Mexican Norm NOM-031-SSA2-1999 for monitoring childrens' health [20]. As in previous studies [15,16,21], the most common BD were congenital heart diseases, especially those of the atrial septum, followed by PDA, which was found as a single malformation (16/52), or as part of a more complex congenital heart disease (11/52) with pulmonic stenosis or tricuspid insufficiency. Ocular malformations were the next most frequent BD. In contrast, no urologic malformations are documented [10]. In this cohort, we found two cases of CH associated with Hirschsprung disease. This association was noted in a previous study, but the nature of the relationship is unknown. Some authors postulate that thyroid hormones may have a direct effect on controlling gene expression, ligand receptors, apoptotic factors, and cellular migration or differentiation [22]. An association between CH and Beckwith–Wiedemann syndrome and Pierre Robin sequence was also documented previously [23], but the pathogenic link between these conditions is unknown [24]. To our knowledge, there are no previous reports of an association between CH and Albright's osteodystrophy, VATER association, or frontonasal dysplasia.
Table 1 Median and range of thyrothropine (TSH) and free thyroxine (fT4).
TSH fT4
Agenesis N = 76
SD
Ectopia N = 106
SD
Goiter N = 2
SD
No etiological diagnoses N = 28
SD
p⁎
98.4 (46–174 UI/mL) 0.3 (0.0–1.8 ng/dL)
32.82 0.33
91.4 (8.2–600 UI/mL) 0.4 (0.0–2.0 ng/dL)
58.88 0.38
88.5 (76–101 UI/mL) 0.2 (0.2–0.2 ng/dL)
17.67 0.0
68.9 (4.7–101 UI/mL) 0.4 (0.1–1.3 ng/dL)
26.54 0.37
0.007⁎ 0.0006⁎
Thyrothropin (TSH) and free thyroxine (fT4) at diagnosis given as median and range for the different etiological groups. Statistical test = Kruskall Wallis. ⁎ p = 0.05.
S. Monroy-Santoyo et al. / Early Human Development 88 (2012) 61–64
Fig. 1. Etiological cause of congenital hypothyroidism (ectopia, agenesis and goiter) expressed as percentage of patients. Within each group, patients were subdivided according to gender and presentation: I = isolated congenital hypothyroidism; CH = congenital hypothyroidism; CH + BD = congenital hypothyroidism associated to birth defects.
Due to the high prevalence and wide spectrum of CH + BD observed in our study, we propose that it would be more beneficial to take a comprehensive clinical diagnostic approach rather than just performing isolated echocardiograms or renal sonograms in CH Table 2 Spectrum of birth defects found in patients with congenital hypothyroidism. PDA ASD Pulmonary stenosis VSD Ophtalmological Strabismus Congenital bilateral cataract Affected III and VI cranial nerves/right palpebral ptosis Skeletal Inferior limbs asymmetry Congenital hip dysplasia Talipes equinovarus Lumbosacral dysraphia Craniofacial Neonatal teeth Facial hemangioma Right microtia Sella Turcica dysplasia Central nervous system Hydrocephalus Frontotemporal agenesis Genital Cryptorchidism Phymosis ASD + VSD Category II Multiple CHD alone VSD + PDA birth defects ASD+PDA+tricuspid insufficiency (n=12) PDA + pulmonary stenosis VSD + tricuspid insufficiency CHD+Ophtalmological PDA + strabismus ASD + strabismus PDA + congenital midriasis CHD + Craniofacial ASD + cleft lip and palate CHD+Gastrointestinal Pulmonary stenosis + hepatic hemangioendothelioma Craniofacial+ Right microtia + strabismus Ophthalmological Cleft palate + dermoid cyst Hirschsprung disease Category III Albright's hereditary osteodystrophy Syndromes or Pierre Robin sequence diseases Beckwith Wiedemann syndrome (n=7) VATER association Frontonasal dysplasia Category I Single birth defect (n=33)
Congenital heart disease (CHD)
63
patients. A weakness of our study is the possible bias caused by its setting, because this population was evaluated and treated in a specialized medical center where doctors have experience detecting BD. Although it is known that patients with CH should be evaluated with greater frequency and diligence, in Mexico this does not always occur, because treatment and monitoring of these patients is sometimes provided by nurses and doctors who are not trained in the detection of associated BD. Clinicians who lack specialized training may be more likely to overlook BD, with a consequently poorer outcome for patients. The mechanism of the association between CH and BD is not fully understood, but previous authors have proposed that a genetic component may interfere with early morphogenesis, causing derangement in several organs and systems [10,11]. The wide variety of BD associated with CH is likely due to the complex nature of organogenesis and the critical role played by thyroid hormones in embryogenesis. It is not yet known whether migration and cell differentiation defects are common to several organs in patients with CH + BD, or if the lack of thyroid hormones is disrupting embryogenesis. Further investigation is required. This work provides data regarding the high prevalence of BD in patients with permanent CH, and showed that thyroid agenesis was the main etiological cause of CH in patients with associated congenital malformations. The high prevalence of CH + BD suggests that there is a need for a more comprehensive clinical diagnostic approach. Conflict of interest statement The authors have no conflicts of interest to declare, and no sources of funding to declare.
8 5 2 1 3 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 1 1 1 1 1
Summary of the BD according to the number (single, multiple, syndrome or disease), type and organ involvement. Abbreviations: PDA: patent ductus arteriosus; ASD: atrial septal defect; VSD: ventricular septal defect; VATER: vertebral defects, anal atresia, esophageal atresia /tracheo-esophageal fistula, renal dysplasia, radial-limb anomalies.
Acknowledgments We want to thank Alejandro González-Garay MD, PhD from the Medical Research Department at the National Institute of Pediatrics for his help with statistical analyses. References [1] Hobbs CA, Cleves MA, Simmons CJ. Genetic epidemiology and congenital malformations: from de chromosome to the crib. Arch Pediatr Adolesc Med 2002;156:315–20. [2] Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis 2010, doi:10.1186/1750-1172-5-17. [3] Lorey FW, Cunningham GC. Birth prevalence of primary congenital hypothyroidism by sex and ethnicity. Hum Biol 1992;64:531–8. [4] Shapira SK, Lloyd-Puryear MA, Boyle C. Future research to identify causes of the increasing incidence rate of congenital hypothyroidism in the United States. Pediatrics 2010;125:S64–8. [5] Polak M, Van Vliet G. Therapeutic approach of fetal thyroid disorders. Horm Res Paediatr 2010;74:1–5. [6] Roberts HE, Moore CA, Fernhoff PM, Brown AL, Khoury1 MJ. Population study of congenital hypothyroidism and associated birth defects, Atlanta, 1979–1992. Am J Med Genet 1997;71:29–32. [7] Bamforth JS, Hughes IA, Lazarus J, John R. Congenital anomalies associated with hypothyroidism. Arch Child Dis 1986;61:608–9. [8] Lazarus JH, Huges IA. Congenital abnormalities and congenital hypothyroidism. Lancet 1988;332:52. [9] Reddy PA, Rajagopal G, Harinarayan CV, Vanaja V, Rajasekhar D, Suresh V, et al. High prevalence of associated birth defects in congenital hypothyroidism. Int J Pediatr Endocrinol 2010, doi:10.1155/2010/940980. [10] Kumar J, Gordillo R, Kaskel FJ, Druschel CM, Woronieck RP. Increased prevalence of renal and urinary tract anomalies in children with congenital hypothyroidism. J Pediatr 2009;154:263–6. [11] Ramos HE, Nesi-França S, Maciel RM. New aspects of genetics and molecular mechanisms on thyroid morphogenesis for the understanding of thyroid dysgenesia. Arq Bras Endocrinol Metabol 2008;52:1403–15. [12] Castanet M, Marinovic D, Polak M, Léger J. Epidemiology of thyroid dysgenesis: the familial component. Horm Res Paediatr 2010;73:231–7. [13] Hinton CF, Harris KB, Borgfeld L, Drummond-Borg M, Eaton R, Lorey F, et al. Trends in incidence rates of congenital hypothyroidism related to select demographic factors: data from the United States, California, Massachusetts, New York, and Texas. Pediatrics 2010;125:s37–47.
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[14] Vela-Amieva M, Gamboa-Cardiel S, Pérez-Andrade M, Ortiz J, González C, Ortega V. Epidemiología del hipotiroidismo congénito en México. Salud Publica Mex 2004;46:141–8. [15] Olivieri A, Stazi MA, Mastroiacovo P, Fazzini C, Medda E, Spagnolo A, et al. 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). J Clin Endocrinol Metab 2002;87:557–62. [16] Siebner R, Merlob P, Kaiserman I, Sack J. Congenital anomalies concomitant with persistent primary congenital hypothyroidism. Am J Med Genet 1992;44:57–60. [17] Kreisner E, Neto EC, Gross JL. High prevalence of extrathyroid malformations in a cohort of Brazilian patients with permanent primary congenital hypothyroidism. Thyroid 2005;15:165–70. [18] Devos H, Rodd C, Gagné N, Laframboise R, Van Vliet G. A search for the possible molecular mechanisms of thyroid dysgenesis: sex ratios and associated malformations. J Clin Endocrinol Metab 1999;84:2502–6.
[19] Fagman H, Nilsson M. Morphogenesis of the thyroid gland. Mol Cell Endocrinol 2010;323:35–54. [20] http://www.salud.gob.mx/unidades/cdi/nom/031ssa29.html. [21] Sabri MR, Shahriari H, Mashemipour M. Congenital cardiac malformations in congenital hypothyroid patients in Isfahan. JRMS 2006;11:234–9. [22] Eren M, Celik M, Kinik S, Arda IS. A case of Hirschsprung disease does thyroid hormone have any effect? Turk J Pediatr 2009;51:94–6. [23] Ramadan GI, Kennea NL. Beckwith–Wiedemann syndrome associated with congenital hypothyroidism in a preterm neonate: a case report and literature review. J Perinatol 2009;29:455–67. [24] Toromanovic A, Tahirovic H. Congenital hypothyroidism associated with neonatal tooth, pierre robin syndrome and congenital heart defects. J Pediatr Endocrinol Metab 2009;22:881–2.
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Higher incidence of thyroid agenesis in Mexican newborns with congenital hypothyroidism associated with birth defects Susana Monroy-Santoyo a, Isabel Ibarra-González b, Cynthia Fernández-Lainez a, Sydney Greenawalt-Rodríguez a, Jorge Chacón-Rey a, Raúl Calzada-León a, Marcela Vela-Amieva a,⁎ a b
Instituto Nacional de Pediatría, Secretaría de Salud, Mexico Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, UNAM, Mexico
a r t i c l e
i n f o
Article history: Received 18 May 2011 Received in revised form 5 July 2011 Accepted 6 July 2011 Keywords: Congenital hypothyroidism Birth defects Newborn screening Congenital malformations Thyroid agenesis
a b s t r a c t Background: Congenital hypothyroidism (CH) is the most common endocrine system disorder in newborns. Ectopic thyroid and agenesis are the most frequent thyroid structural malformations. Several reports have shown that CH is associated with birth defects (BD) ranging from congenital heart disease to ocular and gastrointestinal anomalies. Aims: We investigated how many and what types of BD were associated with CH in Mexican children. Study design: Cross-sectional study conducted in patients with confirmed CH. Setting: Highly specialized government pediatric center in Mexico City. Subjects: We included 212 patients with permanent CH identified by newborn screening. Results: We found that 24% of patients with CH also had BD, and that there was a higher prevalence of thyroid agenesis in the group of patients with CH associated with BD (CH + BD) versus the isolated CH group (p = 0.007). There were more females than males in both groups. The most common BD were congenital heart diseases, especially those of the atrial septum, followed by patent ductus arteriosus, found as a single malformation or as part of a complex congenital heart disease. In this study, we found Hirschsprung disease, Beckwith–Wiedemann syndrome, Pierre Robin sequence, Albright's osteodystrophy, VATER association, and frontonasal dysplasia associated with CH. Conclusions: In this study population, there was a high prevalence of BD in patients with permanent CH. Thyroid agenesis was the main etiological cause of CH in patients with associated congenital malformations. The high prevalence of CH + BD underlines the need for a comprehensive clinical diagnostic approach of the patients with CH. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Birth defects (BD) occur in 3–4% of newborns (NB) worldwide [1]. Congenital hypothyroidism (CH) is the most common disorder of the endocrine system in newborns; it affects 3 in 10,000 NB (1:2000 to 1:4000 NB) [2] and is more common in females [3]. The global prevalence of CH varies widely among biogeographical areas and populations, and there may be associated environmental (nutritional) and genetic factors [4]. In the majority of children with CH the thyroid gland shows structural malformations called thyroid dysgenesis, which includes defects in the differentiation or survival of thyroid follicular cells, which leads to thyroid agenesis or athyreosis in approximately 20% cases of patients with of thyroid dysgenesis, or in the downward migration of the median thyroid anlage during embryonic development, resulting in ⁎ Corresponding author. E-mail address: [email protected] (M. Vela-Amieva). 0378-3782/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2011.07.009
ectopic thyroid in the remaining 80% of patients with thyroid dysgenesis [5]. Several reports have shown a high frequency of CH associated with BD in different populations, ranging from congenital heart disease to ocular and gastrointestinal anomalies [6–8]. Recent studies have proposed that babies with CH should be thoroughly examined to detect BD using techniques such as echocardiography and renal ultrasonography [9,10]. The association between CH + BD is not fully understood, but there may be a genetic component that interferes with early morphogenesis, causing derangement in several organs and systems [11,12]. It is known that CH is more common in Hispanic populations [13]; there are documented rates of eight cases per 10,000 NB in some geographic areas of Mexico [14]. However, there are no data available regarding the association between CH + BD in the Mexican population. Thus, our objective was to investigate how many and what kinds of BD were associated with CH in a highly specialized pediatric hospital setting.
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2. Materials and methods This cross-sectional study was conducted in a convenience sample comprising patients with CH at the National Institute of Pediatrics in Mexico City. After approval by the Institute's investigation and ethics committees, we included the files of Mexican patients diagnosed with CH by newborn screening (NBS) based on thyrotropin levels N10 IU/mL (thyrotropin levels were measured with an enzyme-linked immunosorbent assay) [14]. The CH diagnosis was confirmed by thyroid function tests: thyrotropin (N4 IU/mL), low total triiodothyronine (b72 ng/dL), and low free thyroxine (b0.8 ng/dL). 99mTC radionuclide thyroid scintigraphy was performed before the onset of therapy. An informed consent was signed by the parents of the infants. The recorded CH clinical data included: umbilical hernia, jaundice, dry skin, constipation, characteristic facies, hoarse cry, large posterior fontanel, edema, macroglossia, somnolence, hypotonia, slow feeding, hypothermia, respiratory distress, congenital hip dislocation, heart murmur, and perioral cyanosis. Patients with Down syndrome were excluded from the study, because of the known association of the syndrome with thyroid dysfunction. Preterm newborns with patent ductus arteriosus (PDA) as the only BD present were also excluded, because of this condition's association with premature birth. The patients were clinically examined and classified as follows: [1] Isolated CH (with no BD associated), [2] CH with a single BD, [3] CH with two or more BD, and [4] CH with syndromes or associated diseases. A comparison of proportions to determine statistical significance was performed with MedCalc software version 7.3.0.1 and Stata data analysis and statistical software. A p value of b0.05 was considered to be significant. 3. Results We analyzed the cases of 212 CH infants who were born over a 6-year period (2000–2006). The studied population had the following demographic data: mean maternal age, 26 years (14–44 years); mean number of gestations, 2 [1–8]; and mean gestational age, 39 weeks (29–42 years). Eighty-one patients (44%) were delivered by cesarean section, and 103 (56%) were delivered by uncomplicated vaginal birth. The distribution by sex was 135 (73%) females and 49 (27%) males. The mean birth weight and height were 3183 g (range 1000– 5000 g) and 49.6 cm (range 40–56 cm), respectively. CH in all of the cases was identified by NBS; however, the infants' age upon referral to our center was between 5 days and 4 months. The most prominent clinical data were: umbilical hernia (78%), hoarse cry (67%), jaundice (65%), constipation (63%), macroglossia (56%), hypoactivity (49%), and dry skin (46%). Of the 212 patients, there were 106 patients with ectopic thyroid (77 females and 29 males), 76 with agenesis (57 females and 19 males), two with goiter or dyshormonogenesis (one female and one male), and 28 without feasible etiological diagnoses resulting from radionuclide thyroid scintigraphy (15 females and 13 males). The medians and ranges of TSH and free T4 at diagnosis for these etiological groups are shown in Table 1. The comparison of proportions of both TSH and free T4 among the different etiological groups was statistically significant (p = 0.007 and p = 0.006, respectively) when the group without feasible etiological diagnoses was compared to the other
groups. In this cohort, 160 patients had isolated CH and 52 patients (24%) presented one or more associated BD. Of the CH + BD patients, 33 had only one BD, 12 had two or more BD, and seven had a syndrome or associated disease. Fig. 1 shows the patients classified into two groups: isolated CH and CH + BD. The CH etiology and sex of the patients is also listed in Fig. 1. We found a higher prevalence of thyroid agenesis in the CH + BD group versus the isolated CH group; this comparison was statistically significant (p = 0.007). There were more females than males in all of the groups. Table 2 describes the patients' BD according to their number, syndrome or disease, and affected organ or system. 4. Discussion Our results revealed a high frequency of BD associated with CH (24%). The frequencies found by us and by Roberts et al. [6] are higher than those found by other authors [15–17]. The prevalence of the different forms of thyroid dysgenesis varies depending on the diagnostic tool used for thyroid imaging [18]; however, in our center, the same diagnostic modality ( 99mTc scintigraphy) was performed with all of the participants. The most noticeable finding of our study was the higher prevalence of agenesis as the main etiological cause of CH in the CH + BD group in contrast to the isolated CH group, in which thyroid ectopia was the most common cause. As mentioned previously, thyroid ectopia is the most common cause of isolated CH [18,19]; however, to our knowledge, this is the first study in a Mexican population to find a difference in CH etiology in patients with CH + BD. Interestingly, in this cohort the number of patients with goiter/ dyshormonogenesis was low. The statistically significant difference in THS and free T4 values found between the group of patients without feasible etiological diagnosis and the others, suggests that in the former the goiter/dyshormonogenesis cases may be included as thyroid enlargement is not often detected clinically at birth. There was no difference in the birth weight and height of the newborns in our study compared to the data established by the Official Mexican Norm NOM-031-SSA2-1999 for monitoring childrens' health [20]. As in previous studies [15,16,21], the most common BD were congenital heart diseases, especially those of the atrial septum, followed by PDA, which was found as a single malformation (16/52), or as part of a more complex congenital heart disease (11/52) with pulmonic stenosis or tricuspid insufficiency. Ocular malformations were the next most frequent BD. In contrast, no urologic malformations are documented [10]. In this cohort, we found two cases of CH associated with Hirschsprung disease. This association was noted in a previous study, but the nature of the relationship is unknown. Some authors postulate that thyroid hormones may have a direct effect on controlling gene expression, ligand receptors, apoptotic factors, and cellular migration or differentiation [22]. An association between CH and Beckwith–Wiedemann syndrome and Pierre Robin sequence was also documented previously [23], but the pathogenic link between these conditions is unknown [24]. To our knowledge, there are no previous reports of an association between CH and Albright's osteodystrophy, VATER association, or frontonasal dysplasia.
Table 1 Median and range of thyrothropine (TSH) and free thyroxine (fT4).
TSH fT4
Agenesis N = 76
SD
Ectopia N = 106
SD
Goiter N = 2
SD
No etiological diagnoses N = 28
SD
p⁎
98.4 (46–174 UI/mL) 0.3 (0.0–1.8 ng/dL)
32.82 0.33
91.4 (8.2–600 UI/mL) 0.4 (0.0–2.0 ng/dL)
58.88 0.38
88.5 (76–101 UI/mL) 0.2 (0.2–0.2 ng/dL)
17.67 0.0
68.9 (4.7–101 UI/mL) 0.4 (0.1–1.3 ng/dL)
26.54 0.37
0.007⁎ 0.0006⁎
Thyrothropin (TSH) and free thyroxine (fT4) at diagnosis given as median and range for the different etiological groups. Statistical test = Kruskall Wallis. ⁎ p = 0.05.
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Fig. 1. Etiological cause of congenital hypothyroidism (ectopia, agenesis and goiter) expressed as percentage of patients. Within each group, patients were subdivided according to gender and presentation: I = isolated congenital hypothyroidism; CH = congenital hypothyroidism; CH + BD = congenital hypothyroidism associated to birth defects.
Due to the high prevalence and wide spectrum of CH + BD observed in our study, we propose that it would be more beneficial to take a comprehensive clinical diagnostic approach rather than just performing isolated echocardiograms or renal sonograms in CH Table 2 Spectrum of birth defects found in patients with congenital hypothyroidism. PDA ASD Pulmonary stenosis VSD Ophtalmological Strabismus Congenital bilateral cataract Affected III and VI cranial nerves/right palpebral ptosis Skeletal Inferior limbs asymmetry Congenital hip dysplasia Talipes equinovarus Lumbosacral dysraphia Craniofacial Neonatal teeth Facial hemangioma Right microtia Sella Turcica dysplasia Central nervous system Hydrocephalus Frontotemporal agenesis Genital Cryptorchidism Phymosis ASD + VSD Category II Multiple CHD alone VSD + PDA birth defects ASD+PDA+tricuspid insufficiency (n=12) PDA + pulmonary stenosis VSD + tricuspid insufficiency CHD+Ophtalmological PDA + strabismus ASD + strabismus PDA + congenital midriasis CHD + Craniofacial ASD + cleft lip and palate CHD+Gastrointestinal Pulmonary stenosis + hepatic hemangioendothelioma Craniofacial+ Right microtia + strabismus Ophthalmological Cleft palate + dermoid cyst Hirschsprung disease Category III Albright's hereditary osteodystrophy Syndromes or Pierre Robin sequence diseases Beckwith Wiedemann syndrome (n=7) VATER association Frontonasal dysplasia Category I Single birth defect (n=33)
Congenital heart disease (CHD)
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patients. A weakness of our study is the possible bias caused by its setting, because this population was evaluated and treated in a specialized medical center where doctors have experience detecting BD. Although it is known that patients with CH should be evaluated with greater frequency and diligence, in Mexico this does not always occur, because treatment and monitoring of these patients is sometimes provided by nurses and doctors who are not trained in the detection of associated BD. Clinicians who lack specialized training may be more likely to overlook BD, with a consequently poorer outcome for patients. The mechanism of the association between CH and BD is not fully understood, but previous authors have proposed that a genetic component may interfere with early morphogenesis, causing derangement in several organs and systems [10,11]. The wide variety of BD associated with CH is likely due to the complex nature of organogenesis and the critical role played by thyroid hormones in embryogenesis. It is not yet known whether migration and cell differentiation defects are common to several organs in patients with CH + BD, or if the lack of thyroid hormones is disrupting embryogenesis. Further investigation is required. This work provides data regarding the high prevalence of BD in patients with permanent CH, and showed that thyroid agenesis was the main etiological cause of CH in patients with associated congenital malformations. The high prevalence of CH + BD suggests that there is a need for a more comprehensive clinical diagnostic approach. Conflict of interest statement The authors have no conflicts of interest to declare, and no sources of funding to declare.
8 5 2 1 3 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 1 1 1 1 1
Summary of the BD according to the number (single, multiple, syndrome or disease), type and organ involvement. Abbreviations: PDA: patent ductus arteriosus; ASD: atrial septal defect; VSD: ventricular septal defect; VATER: vertebral defects, anal atresia, esophageal atresia /tracheo-esophageal fistula, renal dysplasia, radial-limb anomalies.
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