International Journal of Cardiology 177 (2014) 6–7
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letters to the Editor
Role of hypocalcemia in identification of 22q11 deletion syndrome among patients with congenital heart defects Vinicius Freitas de Mattos a, Leonardo Paludo Sulczinski b, Olga Gaio Milner b, Filipe Augusto da Silva b, Samir Abou Ghaouche de Moraes b, Patrícia Trevisan c, Marilu Fiegenbaum d, Marileila Varella-Garcia e, Paulo Ricardo Gazzola Zen a,c, Rafael Fabiano Machado Rosa a,c,f,⁎ a
Clinical Genetics, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), RS, Brazil Graduation in Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), RS, Brazil c Graduate Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), RS, Brazil d Human Genetics, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), RS, Brazil e School of Medicine, Division of Medical Oncology, University of Colorado Denver, CO, USA f Clinical Genetics, Hospital Materno Infantil Presidente Vargas (HMIPV), RS, Brazil b
a r t i c l e
i n f o
Article history: Received 15 September 2014 Accepted 25 September 2014 Available online 5 October 2014 Keywords: Calcium Velocardiofacial syndrome Cardiac malformations FISH Screening
The 22q11 deletion syndrome (22q11DS), or Velocardiofacial syndrome, is a common genetic disease caused by deficiency on region 11 on the long arm of chromosome 22. Most patients (N 90%) show a microdeletion usually detectable through fluorescent in situ hybridization (FISH). Currently, over 180 different findings were described, including physical, psychological and behavioral abnormalities [1]. 22q11DS is the second most known cause of congenital heart disease (CHD) [2]. However, due to difficulties in clinical diagnosis and recognition of 22q11DS, as well as high costs related to diagnostic techniques such as FISH, different screening methods have been suggested in populations with CHD. However, their practical application has been proven non-effective [3]. Most patients are identified in neonatal period due to a major CHD associated with hypocalcaemia [1]. Thus, neonatal hypocalcemia is considered one of the cardinal symptoms of 22q11DS [4]. Our aim was ⁎ Corresponding author at: Clinical Genetics UFCSPA/CHSCPA, Rua Sarmento Leite, 245/403, CEP 90050-170 Porto Alegre, RS, Brazil. Tel.: + 55 51 33038771; fax: +55 51 33038810. E-mail address: [email protected] (R.F.M. Rosa).
http://dx.doi.org/10.1016/j.ijcard.2014.09.133 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
to evaluate whether the presence of hypocalcemia could be used as a predictor of 22q11DS among patients with CHD. The sample consisted of a prospective cohort of consecutive patients with CHD. We included only patients hospitalized for the first time in a cardiac intensive care unit of a pediatric referral hospital in South Brazil. The patients evaluated in our sample were described in a previous study developed by Rosa et al. [5]. They underwent cytogenetic evaluation through high-resolution karyotype and FISH for 22q11 microdeletion, and determination of calcium levels in blood. The sampling usually occurred before or soon after surgical procedures and cardiac catheterization. Patients who did not get the calcium dosages were excluded from our analysis. Furthermore, cases with chromosomal abnormalities other than 22q11DS were excluded. The measurement of ionic calcium was performed using the method of ion-selective electrode and the level of total calcium was performed using an automated colorimetric method. Hypocalcemia was considered when the dosage of ionic calcium was below 4 mg/dL or the dosage of total calcium was below 8.5 mg/dL. We also evaluated the report of hypocalcemia history previously or still during the hospitalization. Data analyses were performed using SPSS for Windows (version 18.0). For comparison of frequencies and medians, the statistical tests used were Chi-square, two-tailed Fisher's exact test and Mann–Whitney test. To check if the laboratorial evidence of hypocalcemia at the moment of the hospitalization or even the report of hypocalcemia in another moment could be a marker for 22q11DS, we also calculated the sensitivity, specificity, positive predictive value, negative predictive value and ROC (receiver operating characteristics) curve for these variables. Values of P b 0.05 were considered as statistically significant. This study was approved by the Ethics Committee of the Institution. Informed consent was obtained from all patients. Therefore, among 198 patients evaluated by karyotyping and FISH, 28 had other chromosomal abnormalities, different from 22q11DS. Furthermore, 11 patients did not undergo calcium dosages. Thus, our final sample consisted of 159 patients. Of these, 54.7% were male, and the median of age was 219 days (interquartile range: from 18 to 1168 days). Most patients were hospitalized for heart surgery (79.2%),
V.F. de Mattos et al. / International Journal of Cardiology 177 (2014) 6–7
cardiac evaluation (14.5%) and cardiac catheterization (5%). Four patients (2.5%) had a 22q11 microdeletion. They consisted of two patients with tetralogy of Fallot, one with atrial septum defect (ASD) and one with ventricular septal defect. The dosage of ionic calcium was obtained in 146 patients and the dosage of total calcium was obtained in other 13. The median dosage of ionic calcium was 5 mg/dL (interquartile range: from 4.7 to 5.2) and the mean of total calcium was 10.2 mg/dL (standard deviation: 0.57). Hypocalcemia was verified in 6 patients (3.8%), none of them with 22q11 microdeletion. However, when we considered the report of hypocalcemia previously or during the hospitalization, we verified that additionally only one patient with 22q11 microdeletion presented it. Thus, regarding laboratorial evidence of hypocalcemia at the moment of hospitalization as a diagnostic marker for 22q11DS, its sensitivity, specificity, positive predictive value, negative predictive value and ROC curve could not be calculated, because none of the patients with 22q11 microdeletion presented this finding. However, we could calculate this variable for history of hypocalcemia (including at the moment or previous hospitalization): its sensitivity was 25%, specificity was 96.1%, positive predictive value was 14.3% and negative predictive value was 98%. ROC curve demonstrated an area of 0.394 (null hypothesis: 0.5; P = 0.471) (Fig. 1). The 22q11DS is a well-defined cause of CHDs and is described in 1% to 19% of those patients [5]. The frequency found in our study (2.5%) was very similar to that described in a large Danish study with 2952 children who had CHDs (1.9%) [6]. Hypocalcemia is the main endocrine manifestation in 22q11DS and is often described in the neonatal period [1]. It occurs at some point in
7
the life of about 35–80% of all affected individuals [4,7,8]. When hypocalcemia is present, it is often caused by hypoparathyroidism due to congenital hypoplasia or autoimmune destruction of the parathyroid gland [9]. Hypoparathyroidism is often transitory and unnoticed, ceasing after neonatal period, however, it can manifest later in life as hypocalcemia episodes especially in triggering situations, such as infectious diseases and surgeries [4]. Thus, hypocalcemia could be a marker for screening and selection of patients to be tested for 22q11DS. However, this hypothesis was not confirmed in our sample, since this marker has showed low sensitivity (25%) and the ROC curve area was less then 0.5, indicating that it was an unsatisfactory method. Only one of the four patients with 22q11DS in our sample presented a positive history for hypocalcemia. This was the patient who had the ASD and presented hypocalcemia episodes at three months of age, after a surgical procedure for a subglottic membrane. This case was described by Rosa et al. [10]. However, we cannot exclude the possibility that the low number of patients with 22q11DS in our study may have presented some influence over the verified results. Therefore, despite being a cardinal symptom of 22q11DS [4], hypocalcemia does not seem to be an effectual marker for identification of individuals with the syndrome among carriers of CHDs. Financial support None. Conflict of interests None. References
Fig. 1. Receiver operating characteristics (ROC) curve presented by the screening criteria of family history of hypocalcemia. The area of 0.394 (below 0.5; P = 0.471) indicated that this screening criteria was not satisfactory for 22q11 microdeletion detection.
[1] Rosa RM, Zen PG, Roman T, Graziadio C, Paskulin GA. Síndrome de deleção 22q11.2: compreendendo o CATCH22. Rev Paul Pediatr 2009;27:211–20. [2] Rosa RFM, Zen PRG, Graziadio C, Paskulin GA. 22q11.2 deletion syndrome and congenital heart defects. Rev Paul Pediatr 2011;29:251–60. [3] Rosa RF, Rosa R, Trevisan P, et al. Screening for 22q11 deletion syndrome among patients with congenital heart defects. Sao Paulo Med J 2014;132:125–6. [4] Cancrini C, Puliafito P, Digilio MC, et al. Clinical features and follow-up in patients with 22q11.2 deletion syndrome. J Pediatr 2014;164:1475–80 [e2]. [5] Rosa RFM, Pilla CB, Pereira VLB, et al. 22q11.2 deletion syndrome in patients admitted to a cardiac pediatric intensive care unit in Brazil. Am J Med Genet A 2008;146A: 1655–6. [6] Agergaard P, Olesen C, Ostergaard JR, Christiansen M, Sorensen KM. The prevalence of chromosome 22q11.2 deletions in 2478 children with cardiovascular malformations. A population-based study. Am J Med Genet A 2012;158A:498–508. [7] Repetto GM, Guzmán ML, Puga A, et al. Clinical features of chromosome 22q11.2 microdeletion syndrome in 208 Chilean patients. Clin Genet 2009;76:465–70. [8] Cheung EN, George SR, Costain GA, et al. Prevalence of hypocalcemia and its associated features in 22q11.2 deletion syndrome. Clin Endocrinol 2014;81:190–6 [Oxf]. [9] Lima K, Abrahamsen TG, Wolff AB, et al. Hypoparathyroidism and autoimmunity in the 22q11.2 deletion syndrome. Eur J Endocrinol 2011;165:345–52. [10] Rosa RF, Rosa R, Krumenauer RC, Varella-Garcia M, Paskulin GA. Anterior laryngeal membrane and 22q11 deletion syndrome. Braz J Otorhinolaryngol 2011;77:540.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letters to the Editor
Role of hypocalcemia in identification of 22q11 deletion syndrome among patients with congenital heart defects Vinicius Freitas de Mattos a, Leonardo Paludo Sulczinski b, Olga Gaio Milner b, Filipe Augusto da Silva b, Samir Abou Ghaouche de Moraes b, Patrícia Trevisan c, Marilu Fiegenbaum d, Marileila Varella-Garcia e, Paulo Ricardo Gazzola Zen a,c, Rafael Fabiano Machado Rosa a,c,f,⁎ a
Clinical Genetics, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), RS, Brazil Graduation in Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), RS, Brazil c Graduate Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), RS, Brazil d Human Genetics, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), RS, Brazil e School of Medicine, Division of Medical Oncology, University of Colorado Denver, CO, USA f Clinical Genetics, Hospital Materno Infantil Presidente Vargas (HMIPV), RS, Brazil b
a r t i c l e
i n f o
Article history: Received 15 September 2014 Accepted 25 September 2014 Available online 5 October 2014 Keywords: Calcium Velocardiofacial syndrome Cardiac malformations FISH Screening
The 22q11 deletion syndrome (22q11DS), or Velocardiofacial syndrome, is a common genetic disease caused by deficiency on region 11 on the long arm of chromosome 22. Most patients (N 90%) show a microdeletion usually detectable through fluorescent in situ hybridization (FISH). Currently, over 180 different findings were described, including physical, psychological and behavioral abnormalities [1]. 22q11DS is the second most known cause of congenital heart disease (CHD) [2]. However, due to difficulties in clinical diagnosis and recognition of 22q11DS, as well as high costs related to diagnostic techniques such as FISH, different screening methods have been suggested in populations with CHD. However, their practical application has been proven non-effective [3]. Most patients are identified in neonatal period due to a major CHD associated with hypocalcaemia [1]. Thus, neonatal hypocalcemia is considered one of the cardinal symptoms of 22q11DS [4]. Our aim was ⁎ Corresponding author at: Clinical Genetics UFCSPA/CHSCPA, Rua Sarmento Leite, 245/403, CEP 90050-170 Porto Alegre, RS, Brazil. Tel.: + 55 51 33038771; fax: +55 51 33038810. E-mail address: [email protected] (R.F.M. Rosa).
http://dx.doi.org/10.1016/j.ijcard.2014.09.133 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
to evaluate whether the presence of hypocalcemia could be used as a predictor of 22q11DS among patients with CHD. The sample consisted of a prospective cohort of consecutive patients with CHD. We included only patients hospitalized for the first time in a cardiac intensive care unit of a pediatric referral hospital in South Brazil. The patients evaluated in our sample were described in a previous study developed by Rosa et al. [5]. They underwent cytogenetic evaluation through high-resolution karyotype and FISH for 22q11 microdeletion, and determination of calcium levels in blood. The sampling usually occurred before or soon after surgical procedures and cardiac catheterization. Patients who did not get the calcium dosages were excluded from our analysis. Furthermore, cases with chromosomal abnormalities other than 22q11DS were excluded. The measurement of ionic calcium was performed using the method of ion-selective electrode and the level of total calcium was performed using an automated colorimetric method. Hypocalcemia was considered when the dosage of ionic calcium was below 4 mg/dL or the dosage of total calcium was below 8.5 mg/dL. We also evaluated the report of hypocalcemia history previously or still during the hospitalization. Data analyses were performed using SPSS for Windows (version 18.0). For comparison of frequencies and medians, the statistical tests used were Chi-square, two-tailed Fisher's exact test and Mann–Whitney test. To check if the laboratorial evidence of hypocalcemia at the moment of the hospitalization or even the report of hypocalcemia in another moment could be a marker for 22q11DS, we also calculated the sensitivity, specificity, positive predictive value, negative predictive value and ROC (receiver operating characteristics) curve for these variables. Values of P b 0.05 were considered as statistically significant. This study was approved by the Ethics Committee of the Institution. Informed consent was obtained from all patients. Therefore, among 198 patients evaluated by karyotyping and FISH, 28 had other chromosomal abnormalities, different from 22q11DS. Furthermore, 11 patients did not undergo calcium dosages. Thus, our final sample consisted of 159 patients. Of these, 54.7% were male, and the median of age was 219 days (interquartile range: from 18 to 1168 days). Most patients were hospitalized for heart surgery (79.2%),
V.F. de Mattos et al. / International Journal of Cardiology 177 (2014) 6–7
cardiac evaluation (14.5%) and cardiac catheterization (5%). Four patients (2.5%) had a 22q11 microdeletion. They consisted of two patients with tetralogy of Fallot, one with atrial septum defect (ASD) and one with ventricular septal defect. The dosage of ionic calcium was obtained in 146 patients and the dosage of total calcium was obtained in other 13. The median dosage of ionic calcium was 5 mg/dL (interquartile range: from 4.7 to 5.2) and the mean of total calcium was 10.2 mg/dL (standard deviation: 0.57). Hypocalcemia was verified in 6 patients (3.8%), none of them with 22q11 microdeletion. However, when we considered the report of hypocalcemia previously or during the hospitalization, we verified that additionally only one patient with 22q11 microdeletion presented it. Thus, regarding laboratorial evidence of hypocalcemia at the moment of hospitalization as a diagnostic marker for 22q11DS, its sensitivity, specificity, positive predictive value, negative predictive value and ROC curve could not be calculated, because none of the patients with 22q11 microdeletion presented this finding. However, we could calculate this variable for history of hypocalcemia (including at the moment or previous hospitalization): its sensitivity was 25%, specificity was 96.1%, positive predictive value was 14.3% and negative predictive value was 98%. ROC curve demonstrated an area of 0.394 (null hypothesis: 0.5; P = 0.471) (Fig. 1). The 22q11DS is a well-defined cause of CHDs and is described in 1% to 19% of those patients [5]. The frequency found in our study (2.5%) was very similar to that described in a large Danish study with 2952 children who had CHDs (1.9%) [6]. Hypocalcemia is the main endocrine manifestation in 22q11DS and is often described in the neonatal period [1]. It occurs at some point in
7
the life of about 35–80% of all affected individuals [4,7,8]. When hypocalcemia is present, it is often caused by hypoparathyroidism due to congenital hypoplasia or autoimmune destruction of the parathyroid gland [9]. Hypoparathyroidism is often transitory and unnoticed, ceasing after neonatal period, however, it can manifest later in life as hypocalcemia episodes especially in triggering situations, such as infectious diseases and surgeries [4]. Thus, hypocalcemia could be a marker for screening and selection of patients to be tested for 22q11DS. However, this hypothesis was not confirmed in our sample, since this marker has showed low sensitivity (25%) and the ROC curve area was less then 0.5, indicating that it was an unsatisfactory method. Only one of the four patients with 22q11DS in our sample presented a positive history for hypocalcemia. This was the patient who had the ASD and presented hypocalcemia episodes at three months of age, after a surgical procedure for a subglottic membrane. This case was described by Rosa et al. [10]. However, we cannot exclude the possibility that the low number of patients with 22q11DS in our study may have presented some influence over the verified results. Therefore, despite being a cardinal symptom of 22q11DS [4], hypocalcemia does not seem to be an effectual marker for identification of individuals with the syndrome among carriers of CHDs. Financial support None. Conflict of interests None. References
Fig. 1. Receiver operating characteristics (ROC) curve presented by the screening criteria of family history of hypocalcemia. The area of 0.394 (below 0.5; P = 0.471) indicated that this screening criteria was not satisfactory for 22q11 microdeletion detection.
[1] Rosa RM, Zen PG, Roman T, Graziadio C, Paskulin GA. Síndrome de deleção 22q11.2: compreendendo o CATCH22. Rev Paul Pediatr 2009;27:211–20. [2] Rosa RFM, Zen PRG, Graziadio C, Paskulin GA. 22q11.2 deletion syndrome and congenital heart defects. Rev Paul Pediatr 2011;29:251–60. [3] Rosa RF, Rosa R, Trevisan P, et al. Screening for 22q11 deletion syndrome among patients with congenital heart defects. Sao Paulo Med J 2014;132:125–6. [4] Cancrini C, Puliafito P, Digilio MC, et al. Clinical features and follow-up in patients with 22q11.2 deletion syndrome. J Pediatr 2014;164:1475–80 [e2]. [5] Rosa RFM, Pilla CB, Pereira VLB, et al. 22q11.2 deletion syndrome in patients admitted to a cardiac pediatric intensive care unit in Brazil. Am J Med Genet A 2008;146A: 1655–6. [6] Agergaard P, Olesen C, Ostergaard JR, Christiansen M, Sorensen KM. The prevalence of chromosome 22q11.2 deletions in 2478 children with cardiovascular malformations. A population-based study. Am J Med Genet A 2012;158A:498–508. [7] Repetto GM, Guzmán ML, Puga A, et al. Clinical features of chromosome 22q11.2 microdeletion syndrome in 208 Chilean patients. Clin Genet 2009;76:465–70. [8] Cheung EN, George SR, Costain GA, et al. Prevalence of hypocalcemia and its associated features in 22q11.2 deletion syndrome. Clin Endocrinol 2014;81:190–6 [Oxf]. [9] Lima K, Abrahamsen TG, Wolff AB, et al. Hypoparathyroidism and autoimmunity in the 22q11.2 deletion syndrome. Eur J Endocrinol 2011;165:345–52. [10] Rosa RF, Rosa R, Krumenauer RC, Varella-Garcia M, Paskulin GA. Anterior laryngeal membrane and 22q11 deletion syndrome. Braz J Otorhinolaryngol 2011;77:540.
