Macrothrombocytopenia as Diagnosis Predictor of 22q11 Deletion Syndrome Among Patients with Congenital Heart Defects Patrı´cia Trevisan,1 Sı´lvia Barbosa,2 Graziela Sperotto,3 Caroline Costi,3 Reinaldo L. de Omena Filho,4 Alessandra P. da Silva,4 Marileila Varella-Garcia,5 Marilu Fiegenbaum,6 Rafael F. M. Rosa,1,2,4,7 and Paulo R. G. Zen1,2,4* 1

Graduate Program in Pathology, Universidade Federal de Cieˆncias da Sau´de de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil


Cytogenetics Laboratory, UFCSPA, Porto Alegre, RS, Brazil


Graduation in Medicine, Universidade Luterana do Brasil (ULBRA), Porto Alegre, RS, Brazil Clinical Genetics, UFCSPA and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Porto Alegre, RS, Brazil

4 5

School of Medicine, Division of Medical Oncology, University of Colorado Denver, Denver, Colorado


Human Genetics, UFCSPA, Porto Alegre, RS, Brazil Clinical Genetics, Hospital Materno Infantil Presidente Vargas (HMIPV), Porto Alegre, RS, Brazil


Manuscript Received: 29 May 2013; Manuscript Accepted: 16 February 2014

TO THE EDITOR: The 22q11.2 deletion syndrome (22q11DS), or velocardiofacial/ DiGeorge syndrome is considered one of the most common genetic diseases in humans. Its prevalence has been estimated at 1:2,000– 6,000 births. It is a condition characterized by a broad phenotypic spectrum, with more than 180 different clinical findings described so far. And none of them is considered pathognomonic or present in 100% of cases, which greatly complicates its identification [Rosa et al., 2008, 2009]. The 22q11DS is considered the second most common known cause of congenital heart disease (CHD) [Rosa etal., 2011a].Therefore, some authorshave suggested inthe literature different techniques of screening for 22q11DS within this population in order to optimize the diagnosis of the patients [Tobias et al., 1999; Buttsetal.,2005;Pierpontetal.,2007].However,theseapproachesdo not appear to be cost effective since many patients usually need to be tested and the diagnostic technique (in this case, fluorescence in situ hybridization—FISH) is an expensive method [Rosa et al., 2011a]. Studies have shown that platelet abnormalities, such as thrombocytopenia and larger platelets are frequent among patients with 22q11DS, and that these could serve as a potential clinical marker for the syndrome [Van Geet et al., 1998; Lazier et al., 2001; Naqvi et al., 2011; Rosa et al., 2011b]. Thus, our objective was to evaluate whether macrothrombocytopenia could be considered a diagnosis predictor for 22q11DS among patients with CHD. Our sample was composed of the patients that belonged to the study developed by Rosa et al. [2008]. This consisted of a prospective cohort of consecutive patients with CHD hospitalized in a cardiac intensive care unit of a pediatric referral hospital in the South Brazil. We included only patients at their first hospitalization. These underwent cytogenetic evaluation through high-resolution karyotype and research of 22q11 microdeletion by FISH, as well as

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How to Cite this Article: Trevisan P, Barbosa S, Sperotto G, Costi C, de Omena Filho RL, da Silva AP, VarellaGarcia M, Fiegenbaum M, Rosa RFM, Zen PRG. 2015. Macrothrombocytopenia as diagnosis predictor of 22q11 deletion syndrome among patients with congenital heart defects. Am J Med Genet Part A 167A:1406–1408.

hematological evaluation by counting and determining the volume of platelets. Patients where these testings were not successfully obtained as well as in cases where it has identified the presence of chromosomal abnormalities other than 22q11DS were excluded from the study. CHDs were classified into cyanotic or not. The hematologic evaluation was performed in the absence of conditions that could be related to platelet changes such as sepsis, viral infections, and medications that induce thrombocytopenia. The sampling usually occurred before surgical procedures and cardiac catheterization. Patients who had thrombocytopenia to the point of prevent the performance of these procedures were not excluded 

Correspondence to: Paulo Ricardo Gazzola Zen, Clinical Genetics, UFCSPA/CHSCPA, Rua Sarmento Leite, 245/403, CEP: 90050-170, Porto Alegre, RS, Brazil. E-mail: [email protected] Article first published online in Wiley Online Library ( 21 April 2015 DOI 10.1002/ajmg.a.36531



FIG. 1. Graphic comparing the platelet counts between the patients with and without the 22q11 microdeletion.

from the study. It was considered as thrombocytopenia when the platelet counts were below 150,000/mL and increased platelet volume (larger platelets) when the volume of the platelets was higher than 10 fL. Processing and data analysis were performed using SPSS for Windows (version 18.0) (Chicago, IL). The statistical tests used were Chi-square, two-tailed Fisher’s exact test and Mann–Whitney

1407 test for comparison of frequencies and medians. In order to check if the macrothrombocytopenia could be a clinical marker for identifying patients with 22q11DS, we also calculated the sensitivity, specificity, positive predictive value, negative predictive value and ROC (receiver operating characteristics) curve for this variable. Values of P < 0.05 were considered as statistically significant. Thus, of the 198 patients evaluated by karyotyping and FISH, 28 had other chromosomal abnormalities, different from 22q11DS. Of the remaining 170 patients, 13 did not have the results of the hematological evaluation of the platelets. Thus, our final sample consisted of 157 patients. Of these, 56.7% were male, and the median of age was 296 days. Most patients were hospitalized for heart surgery (76.4%), cardiac evaluation (13.4%), and cardiac catheterization (8.9%). Four patients (2.5%) had a 22q11 microdeletion. Cyanotic heart disease was observed in 59 patients (37.6%). Two of the four patients with 22q11 microdeletion (50%) had this type of heart defect. The median platelet count in the total sample was 324,000/mL (interquartile range: from 250,500 to 401,500). Patients with cyanotic CHD presented a statistically higher frequency of thrombocytopenia (P ¼ 0.0026). The median platelet count was statistically similar between the groups with (226,000/mL) and without 22q11DS (324,000/mL) (P ¼ 0.131) (Fig. 1). Larger platelets have been reported in four patients (2.5%), none of them with 22q11 microdeletion. Thrombocytopenia was seen in 11 patients (7%), and one had a 22q11 microdeletion (P ¼ 0.251). Regarding thrombocytopenia as a diagnostic marker for 22q11DS, its sensitivity was 25%, specificity 93.4%, positive predictive value 9% and negative predictive value 97.9%. The area under the ROC curve for this variable was 0.408 (null hypothesis: 0.5, P ¼ 0.529) (Fig. 2).

FIG. 2. Receiver operating characteristics (ROC) curve presented by the screening criteria of thrombocytopenia.

1408 The frequency of 22q11DS found in our study (2.5%) was similar to that observed by Agergaard et al. [2012] (1.9%) in a sample of 2,478 patients with CHD in Denmark. Macrothrombocytopenia has been a finding frequently observed in patients with 22q11DS. For example, Latger-Cannard et al. [2004] evaluating 34 patients with 22q11DS, verified the presence of thrombocytopenia and larger platelets in 35% and 82% of the cases respectively. Macrothrombocytopenia occurs because the vast majority of patients with 22q11DS (>90%) are obligate heterozygotes for the deletion of the gene GP1BB, which is related to the coagulation process [Kato et al., 2003; Lawrence et al., 2003; Akar and Adekile, 2007; Liang et al., 2007; Rosa et al., 2011b]. However, patients with 22q11DS generally do not manifest an increased tendency of bleeding, even during heart surgery, since Bernard–Soulier syndrome, the condition associated to mutations in GP1BB, is an autosomal recessive disease. And the remaining allele of the gene GP1BB (located in the chromosome 22 without the deletion) is normal in the vast majority of patients with 22q11DS [Van Geet et al., 1998; Latger-Cannard et al., 2004; Rosa et al., 2011b]. Thus, although usually it does not have important clinical implications, some studies have shown that thrombocytopenia and increased platelet size (especially >10 fL) are frequent among patients with 22q11DS and could be potentially used as markers for testing the patients for 22q11DS [Lazier et al., 2001; Kato et al., 2003; Latger-Cannard et al., 2004; Naqvi et al., 2011]. Besides, most hospitals in southern Brazil routinely perform these platelet analyzes, which makes easy to access these exams. However, in our sample, none of the patients with 22q11DS showed larger platelets and only 1 (25%) had thrombocytopenia, whereas no difference was found in relation to this last variable between the group with and without the syndrome. Thus, this marker did not show a satisfactory performance as a diagnostic indicator of 22q11DS. This can be proven by ROC curve analysis, which showed an area of less than 0.5. It is also noteworthy in our case with 22q11DS and thrombocytopenia, that this patient had a cyanotic CHD, a type of heart malformation that may be associated with this platelet abnormality [Lill et al., 2006]. This finding was also observed in our own sample, since patients with cyanotic CHD presented a statistically higher frequency of thrombocytopenia. Thus, we do not know for sure in this case if the thrombocytopenia observed in the patient is due to the syndrome or even to the type of heart defect. Thus, despite the macrothrombocytopenia increasingly be considered a finding pertaining to the broad spectrum of 22q11DS, this seems to be a poor marker for the clinical detection of the syndrome among patients with CHD. However, it is important to be aware that our study presents some limitations, especially related to the small number of patients with 22q11DS.

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Macrothrombocytopenia as diagnosis predictor of 22q11 deletion syndrome among patients with congenital heart defects.

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