Haematological Malignancies and Congenital Heart Disease in Down Syndrome

#### **Chapter 7**

## Chromosome Abnormalities in Hematological Malignancies and Its Clinical Significance

*Hariharan Sreedharan*

#### **Abstract**

The latest version of the World Health Organization guidelines focuses mainly on the genetic and cytogenetic features of hematologic neoplasms as predictors of diagnostic, treatment decision, prognostic outcome, and for treatment monitoring in hematological malignancies. There are different techniques to identify these abnormalities. Live cells are needed for chromosome preparation. The Hematological malignancies include myeloid and lymphoid neoplasms. The myeloid neoplasms include Myelodysplastic syndromes, myeloproliferative neoplasms, and acute myeloid leukemias. The Lymphoid neoplasms include acute and chronic lymphocytic leukemias, plasma cell neoplasms, myeloma, hodgkin, and nonhodgkin lymphomas. The first chromosomal abnormality discovered in connection with cancer is the Philadelphia chromosome, which is an abnormal chromosome 22, formed due to the translocation between chromosomes 9 and 22. The presence of this abnormal chromosome confirms the diagnosis of "CML". After that, hundreds of chromosomal abnormalities have been identified in hematological malignancies in different parts of the world. In AML, specific abnormalities were identified as having a good prognosis, intermediate prognosis, and poor prognosis. In other hematological malignancies also there some specific chromosome abnormalities are associated with prognostication. Now a day's clinicians depend mainly on genetic abnormalities for the proper treatment management of hematological malignancies, so the study of chromosomal abnormalities is essential.

**Keywords:** hematological malignancies, chromosomes, abnormalities, cytogenetics, karyotype, leukemia, lymphoma

#### **1. Introduction**

In hematological malignancies, the study of chromosomal abnormalities is essential for the proper diagnosis, prognosis prediction, treatment decision, and treatment monitoring. The important technique used for the study of chromosomal abnormalities are the conventional cytogenetics, the advanced techniques like Fluorescent In situ Hybridization (FISH), Spectral Karyotyping (SKY)/ Multiplex Karyotyping/MFISH, and, to some extent, array comparative genomic hybridization (array CGH), have enhanced the knowledge of chromosome abnormalities in hematologic neoplasms [1]. The cytogenetic study requires the presence of live cells or at least intact nuclei. Human cancer cells divide spontaneously and without culturing, chromosomes could be prepared from the sample [2]. These

techniques have contributed immensely to the discovery of significant cryptic rearrangements in various tissue preparations of leukemia and other cancers. The advanced techniques in cytogenetics FISH, SKY, and CGH are seen as a potential competitor to conventional cytogenetics, due to their higher resolution. Still conventional cytogenetic analysis remains as the best method for the diagnosis of most hematologic neoplasms since it has the advantage of an overall examination of all chromosomes at a glance. Conventional cytogenetics help to identify distinct clonal populations, which are not possible by FISH and practically impossible by array CGH [3, 4].

#### **2. Myeloid neoplasms**

Myelodysplastic syndromes (MDS), Myeloproliferative neoplasms (MPN), MDS/MPN, and acute myeloid leukemias are included in this group. The classification of myeloid neoplasms has recently been modified considering the genetic and cytogenetic abnormalities [5].

#### **2.1 Myelodysplastic syndromes (MDS)**

MDS is a heterogeneous group of hematopoietic neoplasms with an increased risk of transformation into acute myeloid leukemia (AML) via a multistep process [6]. Chromosomal studies are essential for both diagnostic and prognostic information. In about 50% of patients chromosome abnormalities could be observed. The severity of the disease is associated with the frequency of chromosomal abnormalities [7, 8]. About 25% of patients with low-grade MDS, such as refractory anemia and refractory anemia with ring sideroblasts, have an abnormal karyotype, compared with 50–70% of patients with refractory anemia with excess blasts (RAEB-1 and RAEB-2). The karyotypes observed in MDS are variable as they present with single or complex chromosome rearrangements [9, 10]. The most frequent chromosome abnormalities are complete or partial loss of chromosomes 5 and/or 7, deletions on the long arm of chromosome 20, and gain of chromosome 8 [11]. In general, aggressive neoplasms are characterized by more complex karyotypes than those seen in low-grade MDS. Furthermore, as a general rule, dosage aberrations appear to be more represented in primary MDS, whereas balanced translocations are encountered more frequently in secondary MDS. Complex karyotypes with loss/deletion of chromosomes 5 and/or 7 together with deletions of 6p, 12p, and/or 16q are typical in therapy-related MDS, whereas balanced translocations involving 11q23 and 21q22.3 are associated with preceding therapy with DNA topoisomerase II inhibitors [12]. According to the presence of chromosome abnormalities, MDS is classified into different risk groups. 12p-, 9q-, t(15q), 15q-, +21, 5q-, 20q-, -X, -Y, t(19), t(7q), -21 and normal Karyotype are considered as good prognosis. Patients with abnormalities +8,11q-, +18 are included in the Intermediate I group. The presence of abnormalities like t(11q23), any 3q abnormality, +19, 7q-, complex abnormalities (less than 3 abnormalities) are included in the Intermediate II group. Complex abnormalities (more than 3 abnormalities), 3q21.3q26.2, t(5q), 7q/monosomy 7 are considered as poor prognosis [13]. The significance of trisomy 15 with or without the loss of the Y chromosome is not fully understood. Apparently balanced translocations have been reported in MDS, involved with chromosomes 1, 2, 3, 5, 6, 7, 13, 15, 17, 18, 19, and 20 appear to be more frequent, but they appear to be less common than the unbalanced rearrangements [14].

#### **2.2 Myeloproliferative neoplasms (MPNs)**

Myeloproliferative neoplasms are hematopoietic stem cell disorders characterized by the proliferation of one or more myeloid cellular elements in the marrow and mostly affect adult individuals. Chronic myelogenous leukemia (CML), polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), chronic eosinophilic leukemia (CEL), systemic mastocytosis, chronic neutrophilic leukemia (CNL), and the unclassifiable MPNs [5].

#### **2.3 Chronic myelogenous leukemia**

Chronic myelogenous leukemia (CML) is a hematopoietic stem cell disease, most frequently seen in adults. It is characterized by a biphasic or triphasic clinical course in which a benign chronic phase is followed by transformation into an accelerated and blastic phase [15, 16]. The hallmark of CML is the presence of the "Philadelphia chromosome" (Ph), which is the first chromosome abnormality identified to have been associated with a specific malignant neoplasm. The Ph chromosome was first described in 1960 by Nowell and Hungerford and is named after the city in which it was discovered [17]. Because of a reciprocal translocation between chromosome 9 and 22; a major portion from the q arm of chromosome 22 is translocated to the q arm of chromosome 9 and a small portion from the q arm of 9 is translocate the q arm of 22, leads to a shortened chromosome 22, called the Philadelphia chromosome. The t (9;22) (q34;q11.2), leads to the formation of a chimeric transcript between the *ABL1* and *BCR* genes at 9q34 and 22q11.2, respectively [18]. This BCR-ABL fusion gene formed in chromosome 22 is responsible for CML. The main abnormality seen in the chronic phase of CML is t(9;22). Variant translocation due to the involvement of one or more additional chromosomes is observed in about 6% of cases, whereas in approximately 3% of cases the translocation cannot be identified by routine cytogenetics [19]. These variants and cryptic rearrangements generally have the same prognostic outcome of the standard t(9;22), but some are associated with a more aggressive course. Conventional cytogenetic analysis can sometimes reveal abnormalities in addition to the t(9;22). It is important to note, however, that an additional balanced rearrangement in all metaphase cells in chronic phase CML might be constitutional in origin. Additional abnormalities are associated with the accelerated phase or blast crisis, and are characterized by an increase in the number of blasts and worsening of clinical symptoms [20]. The most recurrent chromosome abnormalities (about 90% of cases) in these phases are an additional Ph chromosome, +8, i(17) (q10), and/or +19. Other abnormalities, such as −Y, −7, +21, +19,del(7q), 11q23 del, t(8;21)(q22;q22.3), t(15;17) (q24.1;q21.2), inv. (16)(p13.1q22.1), as well as 3q21.3, 3q26.2, 3 way Ph, 4 way Ph and 11q23 rearrangements have been reported but only in a small number of cases [21].

#### **2.4 Polycythemia vera (PV)**

PV is most commonly seen in men over the age of 50, but anyone can develop PV. These patients typically experience an increased number of white blood cells, an increased platelet count, and an enlarged spleen, especially over time, which in some patients leads to bleeding and thrombosis [22]. About 14–20% of patients with PV have karyotypic abnormalities at the time of initial diagnosis. However, the cytogenetic abnormalities in PV have not been well characterized and their prognosis impact is largely unknown. At the chromosome level, patients are *BCR-ABL* fusion-negative, other abnormalities detected are +1, +8, +9/+9p, and/or del (20q). Furthermore, a gain of 9p is usually the result of a derivative chromosome, the most common of which is a der (9; 18) (p10; q10). This gain is often the result of unbalanced translocations. When the disease progresses abnormalities like del (5q), del (7q), and/or del (17p) appear [23–25].

#### **2.5 Primary myelofibrosis (PM)**

Primary myelofibrosis, also known as idiopathic myelofibrosis and agnogenic myeloid metaplasia, is characterized by an increased number of megakaryocytes and immature granulocytes and associated anemia. Affected patients are generally in their 5th and 6th decade of life [26]. Chromosome abnormalities are observed in about 40–50% of cases at diagnosis. del(13q), del(20q), and gain of chromosome 8 are the commonly seen abnormalities, and additional abnormalities such as del (5q), del (7q), gain of 1q, and del (17p) are detected during disease progression [27].

#### **2.6 Essential thrombocythemia (ET)**

ET is most commonly seen in women over the age of 50, characterized by an increased number of platelets in the peripheral blood. Chromosome abnormalities could be seen in about 10% of cases. The commonly seen abnormalities are +8, +9, del(13q), and del(20q), less commonly gain of 1q, del(5q), and del(7q). As in other MPNs, karyotypic abnormalities are more frequent during disease progression to MDS or AML [28].

#### **2.7 Systemic mastocytosis (SM)**

Systemic mastocytosis, often termed systemic mast cell disease (SMCD), is characterized by infiltration of clonally derived mast cells in different tissues, including bone marrow, skin, the gastrointestinal (GI) tract, the liver, and the spleen [29]. Most Patients with systemic mastocytosis (SM) are characterized by symptoms such as hepatomegaly, osteoporosis, and ascites. This is a very complex disease, as it comprises several distinct entities and is also found in association with neoplasms such as MPN and leukemia [29]. Chromosome abnormalities reported are +8, +9, del(7q), del(11q), del(20q), t(8;21), inv.(16)/t(16;16) and rearrangements involving chromosome 4 [30].

#### **2.8 Chronic neutrophilic leukemia (CNL)**

CNL is a rare *BCR*-*ABL* negative myeloproliferative neoplasm (MPN) characterized by sustained, predominantly mature neutrophil proliferation, bone marrow granulocytic hyperplasia, and hepatosplenomegaly. As the name implies, it is characterized by an increase in the number of mature neutrophils [31]. Approximately 20% of cases have an abnormal karyotype. The abnormalities observed so far include +8, +9, del(11q), del(20q), +21, and less frequently del(12p) [32].

#### **2.9 Chronic myelomonocytic leukemia (CMML)**

CMML happens when monocytes in the bone marrow begin to grow out of control and is characterized by persistent monocytosis and a variable degree of dysplasia [33]. Although no specific abnormality has been associated with CMML, recurrent chromosome abnormalities, such as −7/del(7q), a gain of chromosome 8, and less commonly del(5q), 12p rearrangements, i(17)(q10) and t(5;12) (q33.1;p13.2) have been observed [34].

#### **2.10 Juvenile myelomonocytic leukemia (JMML)**

JMML is a rare MPN that predominantly affects young children under the age of four, characterized by an abnormal proliferation of myelocytes and monocytes in the bone marrow [35]. The most common abnormality is −7/del (7q) and less frequently del(5q). The final diagnosis is based on the exclusion of the translocation 9:22 [36, 37].

#### **2.11 Acute myeloid leukemia (AML)**

AML is characterized by an increase in the number of myeloid cells in the marrow and an arrest in their maturation, frequently resulting in hematopoietic insufficiency, with or without leukocytosis. At least 20% of blasts should be present in the marrow. The classification AML has been revised by the WHO by considering the various genetic and cytogenetic changes. Although AML more frequently affects adults in their 5th decade of life, it has been described in children and young adults also [38]. AML is associated with characteristic recurrent, acquired chromosomal abnormalities, and many are reciprocal translocations that generate a fusion gene, others involve partial or complete loss or gain of a chromosome. Cytogenetic findings are important for the diagnosis and classification of AML and some are associated with distinctive clinicopathologic features, have prognostic significance, and /or influence in the choice of therapy [39]. Recurrent Genetic Abnormalities seen in AML are t(8;21)(q22;q22.3), inv.(16) (p13.1q22.1) or (16;16)(p13.1;q22.1), t(15;17)(q24.1;q21.2), t(9;11)(p22;q23), t(6;9)(p23;q34.1), inv.(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2), and t(1;22)(p13.3;q13.1). As per WHO classification, AML is classified into good, intermediate, and poor prognostic categories according to the presence of specific chromosomal abnormalities [40]. The abnormalities associated with favorable outcome in AML are t(8;21)(q22;q22.3), inv.(16)(p13.1q22.1) or t(16;16)(p13.1;q22.1), t(15;17) (q24.1;q21.2) Intermediate prognosis group include t(9;11)(p21.3;q23.3), adverse group are t(6;9)(p23.1;q34.1), t(v; 11q23.3), t(9;22) (q34.1;q11.2), inv.(3)q21.3;) or t(3;3), −5 or del(5q), −7, −17, abn(17p), complex karyotype and monosomy karyotype. The presence of additional abnormalities in patients with good prognostic features changes the overall disease prognosis. The most frequent additional abnormality in patients with t(8;21) is loss of a sex chromosome (the Y in males), followed by del(9q), del(7q), +8, and/or +21. Other additional chromosome abnormalities seen in patients with inv.(16) include +8, del(7q), and/or + 21and +22 [41, 42]. Acute Promyelocytic Leukemia (APML), is a subtype of AML with the recurrent abnormality t(15;17) (q24.1;q21.2). Originally considered one of the most aggressive leukemias, it is now a model for targeted therapy. Additional abnormalities frequently been observed in *APL*, are +8, del(9q), and del(7q) [43]. In about 5-10 % AML patients, MLL rearrangements at 11q23 could be seen. Among the identified 85 known *MLL* translocations, the majority are of with poor outcomes. Other frequent *MLL* translocation are t(11;19), t(6;11)(q27;q23), t(10;11)(q21.3;q23), inv.(3)(q21.3q26.2) or t(3;3) (q 21.3;q 26.2). The most common additional abnormalities that are seen in cases with rearrangements of 3q21.3 and 3q26.2 are −7 and, less frequently, del(5q) [44, 45].

#### **2.12 Acute megakaryoblastic leukemia (AMKL)**

AMKL is a clonal stem cell neoplasm that comprises between 4%and 15% of newly diagnosed pediatric AML patients [46]. This is commonly regarded as a subtype of AML, with the median age at presentation between 1 and 8 years. AMKL is extremely rare in adults, occurring in only 1% of AML cases. In pediatrics this

disease is divided into two major subgroups: AMKL patients with Down Syndrome (DSAMKL) and AMKL patients without DS (non-DS AMKL). The incidence of developing DS- AMKL is 500 fold higher than in the general population [46]. The main abnormality seen is t (1; 22) which is diagnostic in this group and is considered as with intermediate prognosis. Chromosome abnormalities at diagnosis are observed in about 50% of adult patients and the most common rearrangements seen are in regions 3q21.3 and 3q26.2. Other abnormalities seen frequently are −5/del(5q), −7/del(7q), and +8 [46].

#### **2.13 Myeloid sarcoma (MS)**

Myeloid sarcoma or granulocytic sarcoma is a rare disease that can present as an extramedullary leukemic tumor, concurrently with or at relapse of AML. This is also known as chloroma, although in some rare cases it may present in non-leukemic patients also [47]. MS may be common in patients included in FAB class M2, WHO classification (2016) in a separate entity under 'AML and related neoplasms' and those with cytogenetic abnormalities t(8;21) or inv.(16). The common cytogenetic abnormalities observed in myeloid sarcoma are −7, +8, del(5q), del(20q), +4, +11, del(12p), del(16q), del(13q), del(9p), del(9q), del(6q), del(15q), del(4q), inv.(16)/t(16;16), MLL rearrangements, and t(8;21)(q22;q22.3). The prognosis is variable as it is influenced by several factors including but not limited to age, morphology, and cytogenetic abnormality [48–50].

#### **3. Lymphoid neoplasms**

Lymphoid neoplasms are derived from cells that normally develop into T Lymphocytes or B Lymphocytes (lymphocytes or plasma cells). This includes Acute and chronic lymphocytic leukemias, plasma cell neoplasms, myeloma, Hodgkin and Non-Hodgkin lymphomas. This group of hematologic neoplasms includes immature and mature neoplasms of B-cell, T-cell, and natural killer (NK) cell subtypes [51, 52]. This leukemia is more common in children than in adults. The majority of lymphoid neoplasms (both precursor and mature types) are characterized by recurrent chromosome abnormalities [53].

#### **3.1 Acute lymphoid neoplasms**

This neoplasm is defined as leukemia when it involves the bone marrow and peripheral blood and as lymphoma when it presents as a lesion without evidence of bone marrow and peripheral blood involvement. Approximately 85% of B-ALL patients are children [53–55]. Chromosome abnormalities are useful for prognostic stratification in acute neoplasms. Abnormalities like t(9;22)(q34;q11.2), 11q23 (MLL) rearrangements, t(1;19)(q23.3;p13.3), and hypodiploidy (≤45 chromosomes) in children are known to have an unfavorable prognosis, whereas t(12;21)(p13.2;q22.3) and hyperdiploidy (>50 chromosomes) are associated with a favorable prognostic outcome. t(9;22) (q34;q11.2) appears in approximately 2.5% of children and approximately 25% of adults with B-ALL [56, 57] . Chromosome abnormalities in addition to the t(9;22) are seen in more than 60% of patients, specifically +8 and one extra copy of the Ph chromosome. Other abnormalities seen in B-ALL are −7, +X, and del(9p). MLL translocations are also found BLL which include t(4;11) (q21.3;q23), t(11;19) (q23;p13.3), t(6;11)(q27;q230 and t(9;11)(p22;q23) [58–61]. MLL rearrangements are associated with an unfavorable prognostic outcome in both children and adults. t(1;19)(q23.3;p13.3) is another abnormality that is seen in approximately 5%

#### *Chromosome Abnormalities in Hematological Malignancies and Its Clinical Significance DOI: http://dx.doi.org/10.5772/intechopen.101078*

of children with pre-B-ALL. About 75% of patients show an unbalanced and 25% show a balanced form of this translocation, the unbalanced form in pediatric B-ALL patients is associated with a better prognostic outcome than the balanced form [62]. Three separate groups of hypodiploidy have been observed and are associated with an unfavorable prognosis. The most common is the near-haploid karyotype, with a chromosome count ranging from 26 to 29. The second is with chromosome count ranging from 30 to 39 and the third group with 40 to 44 chromosomes. Generally, a lower number of chromosomes correspond to a worse prognosis. Hyperdiploidy with chromosomes 51 and 55 is found to be associated with a relatively less favorable prognosis than those from 56 to 68 chromosomes. The presence of trisomies 4 and 10 are seemed to be with a better prognosis. The most common gains involve chromosomes 4, 6, 8, 10, 14, 17, 18, 19, and 21. The prognostic outcome of adult B-ALL patients with hyperdiploidy is not as favorable as in children. High hyperdiploidy is associated with poor prognosis [63–65]*.* Another abnormality often seen in children between 2 and 12 years old is the translocation t(12;21)(p13.2;q22.3) and is associated with a long duration of first remission and excellent cure rates. Another abnormality, del(9p) appears to be associated with improved outcomes in adults poor outcomes in children with B-ALL. Abnormalities like, dic(9;20)(p13.2;q11.2), dic(9;12) (p13.2;p12.2), and i(9)(q10), are associated with an excellent prognostic outcome. The most common rearrangements involving 14q32.3 observed in B-ALL are, t(8;14) (q11.2;q32.3), inv.(14)(q11.2q32.3), t(14;14)(q11.2;q32.3), t(14;19) (q32.3;q13.1), and t(14;20)(q32.3;q13.1) [64, 66, 67]. Approximately 10% of adults and 2% of children with B-ALL these translocations are more frequent. A rare translocation t(5;14)(q31.1;q32.3), has also been observed in B-ALL and is usually associated with eosinophilia. Other reported translocations are t(6;14)(p22.3;q32.3) and t(9;14)(p13.2;q32.3). Two cryptic translocations, t(X;14)(p22.3;q32.3) and t(Y;14) (p11.3;q32.3) have recently been described in B-ALL, especially in patients with Down syndrome. The abnormalities were usually seen in T-ALL involve 14q11.2, 7q35, 7p14. A rare but recurrent abnormality seen in T-ALL is inv. (14) (q11.2q32.1) or t(14;14) (q11.2;q32.1) [68–74].

#### **3.2 Non-Hodgkin lymphoma (NHL)**

NHL is a type of cancer that begins in the lymphatic system, comprises a heterogeneous group of disorders characterized by localized proliferation of lymphocytes. In non-Hodgkin's lymphoma, lymphocytes grow abnormally and can form tumors throughout the body. The most reliable criteria for the classification of malignant lymphomas are genetic abnormalities. The most common chromosome anomalies associated with specific lymphomas include t(14;18) (q32.3;q21.3) in follicular lymphoma (FL), t(8;14) (q24.2;q32.3) in Burkitt lymphoma (BL), t(11;14) (q13;q32.3) in mantle cell lymphoma (MCL), and t(11;18)(q21;q21.3) in mucosa-associated lymphoid tissue (MALT) lymphoma [75, 76].

#### **3.3 Follicular lymphoma (FL)**

FL is typically a slow-growing or indolent form of non-Hodgkin lymphoma (NHL) that arises from B-lymphocytes, making it a B-cell lymphoma. This lymphoma subtype accounts for 20–30% of all NHL cases. About 85–90% of patients with FL and 25–30% of patients with diffuse large B-cell lymphoma (DLBCL) exhibit (14;18)(q32.3;q21.3). Variant translocations, such as t(2;18) (p12;q21.3) and t(18;22)(q21.3;q11.2) have been described in both FL and DLBCL. Additional abnormalities in addition to t(14;18), certain numerical abnormalities, specifically trisomies 2, 7, and/or 8, are associated with a more favorable outcome.

Whereas patients with structural abnormalities, specifically del(1p), del(1q), del(6q), +der(18), or del(22q), or gain of an X chromosome or chromosome12, which are associated with an unfavorable outcome. Secondary abnormalities including +7, del(10q), del(6q), and/or +der(18) leads to the progression of FL to DLBCL occurs in 60–80% of cases [77–80].

#### **3.4 Burkitt lymphoma (BL)**

BL is a rare but highly aggressive B-cell NHL. This disease may affect the jaw, central nervous system, bowel, kidneys, ovaries, or other organs. Burkitt lymphoma may spread to the central nervous system (CNS). The most common abnormalities seen are t(8;14)(q24.2;q32.3), which is seen in about 75–80% of patients, t(8;22) (q24.2;q11.2) and t(2;8)(p12;q24.2), which are seen in 10% and 5% of patients, respectively [81, 82].

#### **3.5 Diffuse large B-cell lymphoma (DLBCL)**

DLBCL is the most common type of NHL, accounting for about 22% of newly diagnosed cases of B-cell NHL in the United States. In 25–30% of cases t(14;18) (q32.3;q21.3) is observed. Additional abnormalities seen are rearrangements of 1q and 3q, del(6q), +7, +8, del(10q), del(11q), +12, del(13q), rearrangements of 14q and 17p, +der(18)t(14;18), and +X. The more complex the karyotype the worse the prognostic outcome. Translocations involving 3q27 are found in approximately 35% of patients. More than 30 different partner genes have been translocated with this locus, the most recurrent of which include 2p12, 3q29, 4p13, 6p21.2, 6p22, 7p12, 8q24.2, 11q23, 13q14, 14q32.3, 15q22, 16p13, 17q11.2, 18p11.2, and 22q11.2. Other recurrent abnormalities observed are partial or complete gain of chromosome 3, specifically 3q; loss of chromosome 6; and gain of chromosome 18 and t(14;15) (q32.2;q11.2). Among these abnormalities, the only gain of chromosome 3 is associated with an adverse prognosis [83–88].

#### **3.6 Mantle cell lymphoma (MCL)**

MCL is typically an aggressive, rare form of NHL, in which about 95% of patients exhibit t(11;14)(q13;q32.3). t(2;11)(p12;q13), t(11;22) (q13;q11.2)], have been observed in a limited number of cases, but their detection is equally important for the diagnosis of MCL. t(12;14)(p13;q32;3), t(6;14)(p21;q32.3), t(2;14) (p24;q32.3), partial or complete gain of chromosomes 3 and 8, gain of 15q, and losses of 1p, 8p, 9p, 11q, 13q, loss of 9p, 17p, and gain of 3q and 8q, have also been described in MCL [89–92]*.*

#### **3.7 Mucosa-associated lymphoid tissue (MALT) lymphoma**

This is a slow-growing type of non-Hodgkin lymphoma and, it most commonly develops in the stomach (when it is called gastric MALT lymphoma) but it can develop in other parts of the body also (which is called non-gastric MALT lymphoma). t(11;18)(q21.3;q21.3) is one of the specific chromosome aberrations occurring in 50% of MALT lymphoma cases. When present, this translocation is usually the only chromosome abnormality. The other specific translocation is (14;18)(q32.3;q21.3), which is observed in about 2% of cases. Abnormalities like, t(1;14)(p22.3;q32.3) and its variant t(1;2) (p22.3;p12 and t(3;14)(p13;q32.2) are also been observed [93–95].

*Chromosome Abnormalities in Hematological Malignancies and Its Clinical Significance DOI: http://dx.doi.org/10.5772/intechopen.101078*

#### **3.8 Lymphoplasmacytic lymphoma (LPL)**

This disorder presents with symptoms related to bone marrow infiltration and IgM monoclonal gammopathy. In approximately 50% of LPL cases, the deletion of 6q is observed, followed by a gain of chromosome 4 in 20% of cases, and abnormalities such as del(17p) and gains of chromosomes 3 and 7 in the small number of cases. The prognostic significance of chromosome abnormalities is unclear [96].

#### **3.9 Splenic marginal zone B-cell lymphoma [SMZL]**

SMZL represents a rare chronic B lymphocyte proliferative disease, which only accounts for about 1–2% of non-Hodgkin's lymphoma. Recurrent numerical and structural abnormalities are observed in SMZL. Deletion of 7q is one of the most common structural abnormalities, which is seen in approximately 30–40% of cases. In 30–50% of cases partial or complete trisomy 3 is seen and in 20–30% of cases partial or complete trisomy, 12 is observed. Deletion of 17p is seen in some aggressive cases in addition to these abnormalities [97–100].

#### **3.10 Chronic lymphocytic leukemia (CLL)**

CLL is an indolent B-cell neoplasm that leads to the proliferation of mature, normal-appearing lymphocytes in the peripheral blood, bone marrow, spleen, and lymph nodes. This is a type of non-Hodgkin lymphoma. The most important risk factor for the development of CLL is a positive family history. The prognosis is highly dependent on the presence of recurrent chromosome abnormalities, specifically del(6)(q23.3), del(13q)(q14.3), +12, del(11)(q22.1), and del(17)(p13.1) [101]. The presence of del(13q) is a sole abnormality and is considered as having a good prognosis. The deleted portion of chromosome 13 can vary in size, but it always involves band 13q14.3. Trisomy 12 is considered the second most common abnormality in CLL. Additional abnormality del (13q) is seen along with the gain of chromosome 12 in most cases and less frequently, del(11q) and del(17p), believed to occur mostly as clonal evolution. The presence of +12 together with del(14q) or t(14;18) has also been reported [102–105]. Deletion of 17p is another abnormality associated with loss of *TP53* at 17p13.1, are characterized by a poor response to chemotherapy and short survival*.* The majority of abnormalities leading to del(17p) are unbalanced translocations. Generally, the loss of 17p is present in the context of a complex karyotype. However, a few cases with i(17)(q10) as the only change have been described. Deletion of 6q is rarely the sole abnormality and this abnormality is considered an intermediate marker in CLL. Translocations involved chromosome 14 observed in CLL include t(11;14)(q13.q32.3), t(2;14)(p16.1;q32.3), t(14;19) (q32.3;q13), and t(14;18)(q32.3;q21.3), and their variants [105–110]. Rarely, t(8;14) (q24.2;q11.2) is observed as an additional abnormality in some CLL cases. Another recurrent translocation found to involve chromosome 13 is t(6;13)(p21;q14.1) or t(10;13)(q24;q14) [111, 112]*.*

#### **3.11 B-cell prolymphocytic leukemia**

B-cell prolymphocytic leukemia (B-PLL) is a rare chronic lymphoproliferative neoplasm comprised of prolymphocytes, typically with involvement of the peripheral blood, bone marrow, and spleen, accounting for only 1% of all chronic leukemias of lymphoid origin. The important abnormalities reported are t(11;14), gain

of chromosome 12, and deletions of 6q, 11q, 13q, and 17p, abnormalities. Additional abnormalities seen in some cases of PLL are the t(8;14), t(2;8), and t(8;22)*.* In approximately 50% of cases, rearrangements of chromosome 17 leading to loss of 17p13.1 have been reported [113, 114].

#### **3.12 Hairy cell leukemia (HCL)**

HCL is a rare slow-growing B-cell lymphoproliferative neoplasm that accounts for 2% of all B-cell lymphomas. This affects more men than women, and it occurs most commonly in middle-aged or older adults. There are no specific chromosome abnormalities in HCL. However, a recurrent gain of chromosome 5, specifically the region 5q13-q31, and deletion of chromosome 7, specifically the region 7q22-q36 are demonstrated by conventional cytogenetics. Abnormalities involve chromosomes 1, 6, 14, and 19 are less frequently observed [115, 116].

#### **3.13 Multiple myeloma (MM)**

Multiple myeloma accounts for approximately 12% of hematologic neoplasms. This affects the terminally differentiated plasma cells in the bone marrow and presents with an excess of plasma cells in the bone marrow [117]. Chromosome abnormalities have been crucial in the characterization of prognostically significant markers in MM. Hypodiploidy (<46 chromosomes) with loss of chromosome 13, or chromosome 17, are associated with an unfavorable prognosis. In the majority of cases, the hypodiploid chromosome complement includes structural abnormalities, involving, in particular, chromosomes 1, 4, 6, 14, 16, and 20. Specifically, loss of 1p and/or gain of 1q, losses of 4q and 6q, loss and/or rearrangements of 14q and 16q, and partial or complete loss of chromosome 20 are most commonly seen. Translocations involving chromosome 14, are seen in approximately 85% of the cases, which include translocations, t(4;14)(p16.3;q32.3), t(14;16)(q32.3;q23.1), and t(14;20) (q32.3;q12) which are associated with an unfavorable prognosis. Karyotypes with 70–90 chromosomes and a double content of structural rearrangements, including the relative losses of chromosomes 13 and 17, most likely represent the doubling of a hypodiploid clone. Another group of MM patients is characterized by hyperdiploidy and few or no structural abnormalities. Gains are nonrandom and often involve chromosomes 3, 5, 7, 9, 11, 15, 19, and 21. Patients with the presence of these additional chromosomes are placed in a standard-risk category, as long as there is no deletion of 13q or 17p. The most common translocation in MM is t(11:14)(q13;q32.3) and is present in approximately 25% of cases and is associated with improved prognostic outcomes. The prognostic relevance of hyperdiploid karyotypes might be difficult to ascertain when structural abnormalities are present. An interstitial deletion of 13q, involving either 13q14.2 or 13q14.3, is one of the most common abnormalities in MM and has been detected in over 50% of cases*.* When other abnormalities present along with del(13q) appears to be with a poor prognosis. The prognostic outcome of a hyperdiploid karyotype typically associated with standard-risk myeloma is not altered by the presence of del(13q). On the other hand, in a hypodiploid karyotype, del(13q) or loss of chromosome 13 shows a poor prognosis. In approximately 10% of MM patients deletion of 17p has been observed which leads to deletion of 17p13.1 (*TP53*) and is believed that it occurs as secondary events during disease progression. This deletion is seen in both hypodiploid and hyperdiploid karyotypes. Contrary to what is seen with deletion of 13q, deletion of *TP53* has a negative impact, irrespective of the presence of favorable prognostic markers. Abnormalities involving chromosome 1 in MM include deletions of 1p, gains of 1q, and/or translocations involving either arm.

*Chromosome Abnormalities in Hematological Malignancies and Its Clinical Significance DOI: http://dx.doi.org/10.5772/intechopen.101078*

Deletions of 1p most frequently involve the segment between bands 1p12 and 1p31, whereas gain of 1q involves the segment q21 → qter or the entire long arm. Gain of 1q is the second most frequent chromosomal abnormality seen after del(13q). Among the translocations involving chromosome 1, the majority are derivatives of rearrangements involving various chromosomes, resulting in a gain of 1q. The common recurrent unbalanced translocations leading to gain of 1q are der(1;15) (q10;q10), der(1;16)(q10;p10), and der(1;19) (q10;p10). The most frequent nonrandom chromosomal partners found in translocations with 14q32.3, are t(11;14) (q13;q32.3), t(4;14)(p16.3;q32.3), and t(14;16)(q32.3;q23.1). t(11;14), is detected in about 20–25%, t(4;14)(p16.3;q32.3) is detected in approximately 15% and t(14;16) (q32.3;q23.1) is observed in approximately 5–7% of MM patients. Similarly to t(4;14), tends to occur in hypodiploid karyotypes, together with deletions of 13q and/or 17p, and this abnormality is placed in a high-risk prognostic category. Two other translocations, t(6;14)(p21.1;q32.3) and t(14;20) (q32.3;q12), have also been described in MM [118–126].

#### **3.14 Hodgkin lymphoma (HL)**

HL comprises approximately 30% of all lymphoma cases. HL affects individuals of all age groups with two preferential peaks, one occurring between the ages of 15 and 30 years and the other at 60 years. The majority of HL patients show a normal karyotype, abnormal chromosome complement is found in a minority of cases. There are no specific chromosome abnormalities been detected in HL. The common finding is that the karyotypes tend to be hyperdiploid, with 60–70 chromosomes. There are some recurrent abnormalities which include losses of 1p, 6q, 7q, 13q, 16q, and 17p; gains of 2p, 9p, and chromosome 12, as well as rearrangements of 3q27 [127, 128].

#### **3.15 T-cell prolymphocytic leukemia (T-PLL)**

T-PLL is a rare aggressive malignancy with poor response to conventional treatment and short survival. This affects approximately 2% of adults aged 30 years and over. The most common sites of involvement include peripheral blood, bone marrow, lymph node, and other hematopoietic organs such as the spleen and liver. T-PLL is with distinctive clinical, morphologic, and cytogenetic features. The most common chromosome abnormalities are inv.(14)(q11.2q32.1), t(14;14)(q11.2;q32.1), and t(7;14) (q34;q32.1). The most common translocation in this group is t(X;14)(q28;q11.2). In the majority of cases, additional abnormalities are observed, which include i(8)(q10) or other rearrangements leading to gain of 8q, deletion or rearrangements of 11q, and deletions of 6q, 12p, and 17p [129–131].

#### **3.16 Adult T-cell leukemia/lymphoma (ATLL)**

ATLL is a rare and often aggressive T cell Lymphoma that can be found in the blood (Leukemia), lymph nodes (Lymphoma), skin, or multiple areas of the body. Very complex karyotypes are observed in ATLL patients. The most frequent abnormalities include rearrangements of 7p14.1, 7q34, and 14q11.2; gains of the X chromosomes and chromosomes 3 and 7; rearrangements of 1p, 1q, 2q, 3q, and 17q; and deletions of 6q, 9p, 13q, and 17p. The prognosis associated with these abnormalities is considered an unfavorable prognosis. Abnormalities of 1p, 1q, 3q, and 14q and deletions of 2q, 9p, 14q, and 17p are found to be associated with poor prognosis [132–135].

#### **3.17 Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS)**

PTCL, NOS is a broad category of biologically and clinically heterogeneous diseases that cannot be further classified into any other of the existing entities defined by the WHO classification. Highly complex Karyotypes are usually seen with rearrangements that often lead to losses of 6q, 9p, 10q,13q and gains of 3q, 7q, and 8q and the prognosis is considered as poor for most patients. The t(5;9)(q33.3;q22.2) is an important translocation seen in these lymphomas [136, 137].

#### **3.18 Angioimmunoblastic T-cell lymphoma (AITL)**

AITL is a rare aggressive form of Non-Hodgkin's lymphoma which is a group of related malignancies. This accounts for approximately 2% of all non-Hodgkin's lymphomas but represents the most common subtype (15–20%) of peripheral T-cell lymphomas. Complex Karyotypes are seen and often show a gain of 11q13 and gains of chromosomes 3, 5, and an X chromosome, as well as losses of 5q, 10q, and 12q. Gain of 11q13 may represent a primary event in angioimmunoblastic T-cell lymphoma [138].

#### **3.19 Anaplastic large cell lymphoma (ALCL)**

ALCL is a rare type of NHL and is one of the subtypes of T cell Lymphoma ALCL comprises about 1% of all NHLs and approximately 16% of all T cell lymphomas [127]. The cytogenetic hallmark is the presence of specific translocations involving the anaplastic lymphoma kinase gene (ALK*)* and various partner chromosomes*.* The most common *ALK* translocation is t(2;5)(p23.1;q35.1), which fuses part of the nucleophosmin gene (*NPM1*) located at 5q35.1 with *ALK* located at 2p23.1, leading to activation of *ALK* [139, 140].

#### **Author details**

Hariharan Sreedharan

Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala, India

\*Address all correspondence to: shhrcc@gmail.com; shhrcc@rediffmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Chromosome Abnormalities in Hematological Malignancies and Its Clinical Significance DOI: http://dx.doi.org/10.5772/intechopen.101078*

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#### **Chapter 8**

## Congenital Heart Disease and Surgical Outcome in Down Syndrome

*Zainab Al-Suhaymi*

#### **Abstract**

The prevalence of congenital heart disease has accounted for nearly one-third of all significant congenital anomalies worldwide. The first report about an association between cardiac anomalies and Down Syndrome was in (1876). Ten years after discovering of Down Syndrome and the credit of association between congenital cardiac anomalies and mongolism was suggested in (1894) by Garrod. There many studies performed to identify a correlation between genotype and phenotype in Down Syndrome, little is known about cardiovascular phenotype in Down Syndrome. Congenital heart disease is considered one of the highest causes of mortality and morbidity in Down Syndrome compared to patients with the same lesion of non-down. There is a big debate about surgical management and considered them as risk factors of surgery with precaution and recent technology, Down Syndrome considered as a normal patient in prognosis. This chapter aimed to shed the light on congenital heart disease in Down Syndrome and current knowledge in specific mutations associated with them and how the effect of innovative technology and management to treat them end at the same outcome and sometimes better based on recent research and Scoring System.

**Keywords:** Down Syndrome (DS), congenital heart disease (CHD), genetic mutations, surgical outcome, cardiovascular surgery

#### **1. Introduction**

#### **1.1 History of congenital heart disease in Down Syndrome**

Down Syndrome had a widespread revolutionary widespread interest since the days of Langdon Down's pioneering work in 1866 [1]. The first comprehensive description of this unique syndrome was provided in a short paper published in the London Hospital Reports [2]. Down's article was still unappreciated ten years later. In the July 1876 issue of the *Journal of Mental Science*, other reports on the same subject described the distinguishing features of an apparently new class of "idiots", and the first graphical illustration in the medical literature of DS was drawn in an article by Fraser and Mitchell. This also provided the first pictorial sketch of the facial features of a person with DS [3].

Awareness of DS medical reports was sketchy. It is almost incredible that DS was unknown before the last half of the nineteenth century [4]. In the 1960s,

#### **Figure 1.**

*The child looking over his mother's shoulder could be erroneously diagnosed as being affected with Down syndrome. Sir Joshua Reynolds's painting (1733) entitled Lady Cockburn and Her Children, which hangs in the National Gallery in London.*

Iowa pediatrician Hans Zellweger was excited to find an illustration of a Down patient prior to the latter half of the nineteenth century **Figure 1**. A Down infant appeared in a painting by the Flemish artist Jacob Jordan entitled "Adoration of the Shepherds". This painting is dated 1618 and shows a woman holding a child (probably their daughter, Elizabeth) with similar DS features [5].

Other researchers have searched the art archives to determine pictorial representations of Down patients. In 1968, Dr. Arthur Markingson wrote a letter to the editor of Lancet in which he reported no painting of a Down patient could be found [6]. Dr. Markingson's letter prompted cogent reasons for the apparent rarity of Down children in past centuries. Populations were much smaller than they are now, and the population age structure was different only about two-thirds of females survived to the age at which they could marry. Only half reached the end of childbearing age. Infant mortality was also much higher.

In his opinion, this limited survival of infants with DS in history. In While there were fewer people, the rate of Down births would not have changed appreciably. This suggested that many Down children in the prior centuries did not survive the neonatal period. Thus, raises the question of why did they die? Many reasons must be considered. First, there were no modern therapies such as antibiotics and heart surgery. Down infants often die due to pulmonary infection and heart defects during the critical early years of life. CHD especially likely increased mortality [4–6].

#### **2. Causative gene mutation**

Congenital heart is a major public issue and health challenges. Understanding the molecular genetic mechanism underlying abnormal cardiac lesions associated with trisomy chromosome 21 may lead to novel therapies [7–10]. DS is the most common genetic causes of CHD and characterized by the presence of an extra full or partial human chromosome 21. In recent decades, significant efforts have been made to find the genotype-phenotype correlations for CHD in DS (DS CHD). For earlier detection and prevention and discover a better treatment.

There were several approaches to this problem: generating of a map of partial trisomy (PT21) cases in humans, creating mouse models with different orthologous regions of Hsa21, and analysis of DS gene expression in cells and tissues [11, 12]. Recent studies support the idea that not all Hsa21 loci are required for DS manifestation, suggesting a small region on 21q22.13 is considered critical to the DS core phenotype [13].

A primary goal of genetic studies in DS is to define sub-genomic areas associated with various DS phenotypes. There have been some exciting developments in this area after systematic analysis of 125 subjects from 1973 to 2015 (Pellerin et al., 2016). Retrospective reanalysis of the same cases added seven new topics (Piovesan et al., 2019) [13]. This work built a final map genomic region and discovered 34-kb on the distal part of 21q22.13 highly restricted DS critical region (HR-DSCR). Unfortunately, some patients carried additional chromosomal anomalies which makes the interpretation of genotype-phenotype correlation, including heart defects more difficult. Because of these complications, mice have been used instead of human partial (segmental) Ts21.

The long arm of Hsa21 has 33.9 Mega base in length and contains 430 proteincoding genes; 293 have a homolog in the mouse genome, and only 235 genes are conserved in syntonically regions on mouse chromosomes: (1) 16 (Mmu16, 23.3 Mb, 166 genes), (2) 17 (Mmu17, 1.1 Mb, 22 genes), and (3) 10 (Mmu10, 2.3 Mb, 47 genes). We found that Mmu16 is the only mouse chromosome associated with heart defects in DS [14, 15].

Mouse models associated with congenital heart disease are shown in **Figure 2**. The first is the Tc1 mouse model, which carries Hsa21, where approximately 8% of its genes were deleted leading to heart defects [16, 17]. The second is Ts65D, which is the most widely used model [18]. And exhibits some major DS phenotypes, including heart defects [19, 20]; Ts65Dn is trismic for 13.4 Mb of the 22.9 Mb Hsa21 syntenic region on Mmu16. The cardiovascular phenotype of overlapping in largerthan-5.8 Mb sub-centromeric region on Mmu17, which is not syntactic to any region on Hsa21 [21].

We recently developed new rodent models to understand and mimic DS mouse segmental trisomy. The third type of model is Dp (10)1Yey/+, Dp (16)1Yey/+ and

#### **Figure 2.**

*Representation of the DS mouse models associated with cardiac features. "+" indicates the presence and "-" the absence of phenotypes whereas ND indicates a non-determined state for presence or absence of CHD in Ts1Cje.*

Dp (17)1Yey/+, carrying individual duplications spanning the entire Hsa21 syntenic regions on Mmu10, Mmu16, and Mmu17, respectively. The results showed both Dp (16)1Yey/+Dp (10)1Yey/+; Dp (16)1Yey/+; and Dp (17)1Yey/+ contribute to heart defects with similar frequency. The final model showed heart defect in Dp (16)2Yey/+ embryos within the Tiam1-Kcnj6 region correlated with over-expression of 20 genes in this area [22].

CHD in DS is a phenotype characterized by reducing the extent to which a particular gene or set of genes expressed in the phenotypes of individuals carrying it. Consequently, in PT21 cases mapping, it is possible to exclude chromosomal regions or identify them as critical for the phenotype only in patients with that phenotype (DS CHD). Approaching the DS CHD critical region was proposed by Korenberg et al. [23] when his concept used the 9 Mb region between D21S55 (21q22.2) to the telomere for the first time. This work further used mouse models over 4–5 Mb region, from (D21S55 through MX1) Korbel et al. [24] narrowed down the critical part for DS CHD to 1.77 Mb, **Figure 3**. The region in question was extended from DSCAM to ZNF295 (current name ZBTB21) created from combining the maps of 14 PT21 subjects with CHD with information from segmental trisomic mouse model Dp (16)1Yu/+.

In 40–60% of subjects, the overall risk of DSCHD in DS is from AVSDs [25]. Although some candidate genes have been a cause for DSCHD, conclusive evidence for their involvement is still unknown. We previously reported a map that contains the DSCHD region in humans to a 5.27-Mb chromosomal segment containing 82 genes [26]. **Figure 3A** narrows down this segment to a 2.82-Mb critical region likely involved in DSCHD endocardial cushion defects using an expanded panel with 14 subjects with DSCHD. By integrating our information from segmental trisomic mouse models with DSCHD [16, 21], we integrated a further limit on this region in a particular map (**Figure 3B**); we propose a 1.77-Mb DSCHD critical region, which contains ten genes, including the promoter and a portion of the DS cell adhesion molecule (DSCAM) gene. Specifically, the model Dp (16)1Yu/shows that DSCHD is involved only in the HSA21 regions orthologous to MMU16 (located at 14.4 Mb–42.3 Mb of HSA21); this defines the telomeric DSCHD border and suggests a limited role for the adjacent telomeric region for DSCHD.

#### **2.1 Genes associated with causing CHD**

A multifactorial model used as sample collection. Chromosome 21 Single nucleotide polymorphisms calling and Chromosome 21 Copy number variations analyses by pyrosequencing and Sanger sequencing showed most notable results of this study regarding identifying CHD risk loci in DS [27].


*Congenital Heart Disease and Surgical Outcome in Down Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97134*

#### **Figure 3.**

*A panel of 30 patients with segmental trisomy 21 metanalysis defines DS phenotype candidate regions. Yellow boxes, no phenotype; solid boxes, increased copy-number; open boxes, 1:2 (monosomies) Purple boxes, presence of phenotype. (A) DSCHD region. TOF, tetralogy of Fallot; PS, pulmonic stenosis; PDA, patent ductus arteriosus; VSD, ventricular septal defect; ASD, atrial septal defect; MI, mitral insufficiency. Red box, DSCHD candidate region. Twenty-three subjects have duplications, including the DSCHD region, 14 thereof have DSCHD. No subject lacking a segmental trisomy involving the DSCHD critical regions was diagnosed with DSCHD. Corresponding regions for six mouse models are indicated to the left [21, 22, 39–41]. (B) Proposed DSCHD critical region (red box) determined by combining human and mouse data from A. MMU16 indicates the extent of the duplication in the mouse model Dp (16)1Yu with DSCHD.*

#### **3. Clinical management**

#### **3.1 Diagnostic evaluation**

Echocardiograms are generally accepted as the diagnostic standard. Some studies specified that all had an echocardiogram [49], while others limited by documentation and relied on retrospective review [28]. One study evaluated if screening, chest X-ray and ECG is an effective method to identify which infants with DS should have an echocardiogram. They found that this method resulted in 69 (17%) fewer echocardiograms without missing infants with major CHD [29]. A similar study showed a sensitivity of 71% and a specificity of 91% chest X-ray and ECG soon after birth for three modalities separately or in combination to detect CHD [30].

#### **3.2 Surgical approach**

DS is a challenging public health issue. The survival rate of DS with heart defects has increased dramatically with improved medical care [31]. Infant mortality for

patients with DS remain 5× to 8× higher than that of the general population. In the 1940s to 1960s, the average life expectancy for children born with DS dramatically increased from 12 years in the 1940s to 60 [32]. There has been a gradual improvement in the results of DS children undergoing cardiac surgery in the last 16 years [33] with a better understanding of surgical anatomy, Advances in surgical techniques improved myocardial protection and cardiopulmonary bypass strategies, and advances in postoperative management in the intensive care unit contributed to improved survival rate and decreased mortality [34–36].

When comparing the DS to NS in preoperative data, however there are significant differences in age, RACHS-1 risk category, and presence of substantial noncardiac anomalies among DS patients in the 30 days (about four and a half weeks) to 1 year age group. In contrast, most children in the non-DS patients were in the >1 year age group. The DS population is more likely to have a coexisting major noncardiac structural anomaly, although DS were less likely to have been born prematurely [32].

In open-heart surgery, the cardiopulmonary bypass led to prolonged times. [(110 ± 47 min), 129 (87.75%), and (101.74 ± 33.61)]; aortic cross-clamp was shorter [(65 ± 30 min), 64 minutes (67.21 ± 26.63)]. Depend on the scoring system most patients in DS and Non-DS, RACHS-1 risk categories 1, 2, and 3. Distribution for patients without DS were spread across these three risk categories. In DS, the proportion of patients in risk categories 1, 2, and 3 increased with increasing surgical complexity [32, 37].

Infection is the most common complication that feared by surgeons and results in a more prolonged ICU and hospitalization with considerable treatment in patients with CHD and DS [38]; respiratory complications are also common. Sepsis occurred in 8 patients (10%), mainly caused by Staphylococcus and Pseudomonas. In 7/8 cases, this infection occurred early in the postoperative period. In one case, sepsis developed late and led to death [33].

#### **4. Types of producers associated with DS**

#### **4.1 Favorable surgical outcome**

#### *4.1.1 Complete atrioventricular septal defect*

Hospital mortality ranges from 0.9 to 3% in recent studies [39, 40]. The degree of residual valve dysfunction was independent of surgical choice in a study comparing three surgical techniques [41]. LV outflow tract obstruction is the second cause for reintervention small left ventricle (LV) and a double orifice left the atrioventricular valve. There was an anatomic increase in reoperation incidences, such as a small left ventricle (LV) and a double orifice left atrioventricular valve [41]. The hospital resources usage for cardiac surgery in pediatric patients with CHD and genetic conditions is of great interest [42]. Patients with DS and AVSD heart defect did not constitute an extra financial burden due to good surgical outcome and short hospital stay.

#### *4.1.2 Partial atrioventricular septal defects*

Mortality rate was low (0–1%) and reported with repair performed in early childhood [43]. The left atrioventricular valve anatomy was unfavorable in 31% of cases. Reoperation was required in 22% of non-DS. All patients survived surgery.

Other issues include:

#### *4.1.3 single ventricle physiology and Unbalanced atrioventricular septal defects*

There is often univentricular palliation or correction (Fontan-type) due to the constant risk of pulmonary hypertension or even mildly elevated pulmonary vascular resistance. Excellent survival was noted at palliation when pulmonary vascular resistance was low (<3 Wood Units/m2) in the 1st year of life. The mortality rate of patients with Fontan-type repair was 27.5% in patients with unbalanced AVSD [44]. Moreover, Fontan-type repair was rarely performed and was considered risky (12% early mortality) in Japan [45]. Furukawa et al. reported eight patients with Down syndrome who underwent total cardiopulmonary connection; one patient died, whereas the clinical course and recovery after surgery in the other seven patients was significantly prolonged. They studied 17 patients with DS who underwent TCPC and reported that mortality in the early period was 29% and significantly higher than that in patients without DS (10%). The debate is now DS itself is a vital independent factor of mortality. Future work should evaluate mortality and longterm prognosis.

#### **4.2 Unfavorable surgical outcome**

#### *4.2.1 Tetralogy of Fallot*

Cyanosis in DS patients accounts for about 6% of deaths. Early mortality has been reduced to 1–2% in recent years [39, 46, 47]; pulmonary hypertension is presumed to be a causal factor, and this was supported by its higher incidence in patients with tetralogy of Fallot associated with AVSD. Patients with DS and tetralogy of Fallot need a pulmonary valve replacement (PVR)/implantation earlier than normal patients [48].

#### *4.2.2 Tetralogy of Fallot combined with AVCanal*

This is a rare anomaly frequently associated with DS and low operative risk (4–6%) has been recently accomplished Complete repair [49] two-stage (with prior palliation) and single-stage repair was recently reported. With 10-year survival obtained the two strategies as well as similar freedom from reoperation for left atrioventricular valve regurgitation [50].

### **5. Scoring systems in cardiac surgical outcome**

#### **5.1 RACHS-score**

The RACHS-1 method [51, 52] was used to adjust for differences in the patient mix when comparing in-hospital death. Surgical procedures ranged from 1 to 6 risk categories. Risk category 1 has the lowest risk for in-hospital death, whereas risk category 6 has the highest. Risk categories 5 and 6 were combined for reporting purposes because of the low numbers of patients in each group. Patients with >1 cardiac surgical procedure were placed in the category of the highest risk procedure.

Two studies evaluated outcomes in children with DS by grouping cardiac lesions based on risk-stratified categories (RACHS-1). There were generally low mortality rates for children with DS compared to those without, which highlighting the higher rate of cardiac operations in DS children [32, 39].

#### **5.2 Aristotle score**

A new international Nomenclature of evaluating the quality of care in congenital heart surgery based on the complexity of the surgical procedures the project started in 1999, involving expert surgeons included 50 pediatric surgeons from 23 countries representing International Scientific Societies. The calculation is undertaken in two steps: the first adjusts only the complexity of the procedures by establishing the Basic Score determined by three factors: the potential for morbidity, the anticipated technical difficulty, the potential for mortality. The second step was improving the Comprehensive Score, which further adjusts the complexity according to the specific patient characteristics. The Aristotle method allows the following equation of quality of care: Complexity FN Outcome = Performance which allows precise scoring of the complexity for 145 congenital heart surgery procedures. The complexity was based on the procedures defined by the Society of Thoracic Surgeons (STS)/European Association for Cardiothoracic Surgery (EACTS) [53].

#### **5.3 Propensity score matching analysis**

Propensity score matching was frequently used in the cardiovascular surgery literatures. These methods are increasingly used to reduce the impact of treatmentselection bias in estimating causal treatment effects using observational data [54–56]. Tóth et al. reported that the perioperative values had no significant differences between the DS and non-DS groups after propensity matching. This method used similar values for the variables and can play an essential role in identifying the differences between control and study groups.

In *Seminars in Thoracic and Cardiovascular Surgery,* the propensity score used at 5:1, (NS: DS). PSM based on sex, low birth weight, and prematurity age group with post matching standardized mean difference indicating successful balancing of the two groups; the final matched set was 2493 DS patients. These were compared to 12,465 patients, as shown in **Figure 4**.

We show outcomes after cardiac operations in patients with DS using Texas Inpatient Public Use Datafile was queried for all patients <18 years old undergoing

#### **Figure 4.**

*Children with Down syndrome and non-syndromic children undergoing various cardiac operations represented by The Texas Inpatient Public Use Datafile was queried from 1999 to 2016.*

*Congenital Heart Disease and Surgical Outcome in Down Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97134*

CHD procedures between 1999 and 2016. There were 2,841 cases in DS patients who underwent CHD operations compared to 25,063 non-DS cases. Over the 18-year period. Variables depending on the type of CHD lesion when multiple cardiac lesions require intervention; DS children have an excellent surgical outcome and hospital survival after isolated AVSD than did non-DS children. Bidirectional Glenn palliation TOF/PA repair was associated with worse hospital mortality in children with DS. Further work will be evaluated cardiac and noncardiac comorbidities in DS patients led to higher mortality for specific cardiac lesions [57].

#### **6. Conclusion**

The challenge of cardiac care of DS patients has no more concerns because of a great improving result of cardiac surgery contribute to the increasing survival and to the better quality of life is even more successful and gratifying.

#### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Zainab Al-Suhaymi Resident General Surgery, General Surgery Department, Prince Mohammed Bin Abdul Aziz Hospital, Ministry of National Guard Health Affairs, Al-Madinah, Saudi Arabia

\*Address all correspondence to: zainab.alsuhaymi@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[37] Hoashi T, Hirahara N, Murakami A, Hirata Y, Ichikawa H, Kobayashi J, et al. Current Surgical Outcomes of Congenital Heart Surgery for Patients with Down Syndrome in Japan. Circ J. 2018;82(2):403-8.

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## Section 5

Prenatal Screening, Management and Counseling in Down Syndrome and Other Chromosomal Abnormalities

#### **Chapter 9**

## Prenatal Screening of Aneuploidies

*Madhavilatha Routhu and Shiva Surya Varalakshmi Koneru*

#### **Abstract**

Chromosomal abnormalities includes 1) abnormalities in number of chromosomes which are known as aneuploidies and 2) structural defects like translocations and deletions. In this we will discuss about Aneuploidies The incidence of Aneuploidy is around one in 200 live births. Aneuploidy increases with advancing maternal age. Fetal aneuploidy has been associated with significant pregnancy complications such as growth restriction, congenital malformations and perinatal deaths. Several Major developments are happened in prenatal screening of Aneuploidy especially the introduction of first trimester screen with Nuchal thickness and fetal cell free DNA in maternal plasma and identification of ultrasound markers and biochemical screening in second trimester. In this chapter we will discuss about what are trisomies, why "Down syndrome" is important to detect prenatally, history of "Down syndrome", advances in screening methods biochemical as well as sonographic markers in first and second trimester and the criteria to get those markers. What are the features of trisomy 21, trisomy18 and trisomy13.

**Keywords:** Aneuploidies 1, "Down syndrome" 2, ultrasound markers 3, Nuchal translucency 4

#### **1. Introduction**

Aneuploidies are Trisomy21 ("Down syndrome", T21), Trisomy18 (Edward syndrome, T18), trisomy13 (Patau syndrome, T13), monosomy (turner syndrome, monosomy) and triploidy. "Down syndrome" is more focused than other aneuploidy due to Trisomy 13 and 18 are lethal, do not have very long-term consequences, and almost all cases have major structural abnormalities and can be identified on the basis of these features. Where as in T21 the ultrasound and laboratory findings are subtle and nonspecific. Special effort has to be made to identify these nonspecific features and analyse their importance. Identification of T21 is based on these subtle abnormal structures i.e., ultrasound markers and abnormal biochemistry (low PAPP-A and raised β-HCG). The abortion rate in monosomy X is 98% and Edwards is 86% whereas "Down syndrome" is only 30%. Not only this Downs is the commonest congenital cause of mental disability with long life span and need life-long family support. The incidence is 1in 800 pregnancies. Downs can lead to considerable ill health, although some individual may have only mild problems and can lead relatively normal lives. Having baby with "Down syndrome" is likely to have significant impact on family life. There is currently no known cure. A significant number of parents would opt for terminating such a pregnancy or if they want to continue prior information would benefit for

preparing for such a baby. Downs occur due to non-disjunction type (Errors in meiosis). Translocation type and mosaic type which is rare.

#### **2. History**

In 1862 & 1887 Langdon Down noted that common characteristics of patients with trisomy 21 are skin deficient in elasticity, giving the impression of being too large for the body, and face is flat, broad and destitute of prominence. The cheeks are roundish and extended laterally. The eyes are obliquely placed, and internal canthi more than normally distanced from one another. The palpebral fissure is very narrow. The tongue is long, thick and much roughened. The nose is small. In 1987 B Benacerraf [1], told that this loose skin can be seen in mid trimester scan at 20 weeks as a thickening of skin at the back of neck in axial view of skull in trans cerebellar plane which was defined as nuchal fold. After 5 years it was realized that the excess skin of individuals with Down's syndrome can be visualized by ultrasonography as increased nuchal translucency in the third month of intrauterine life [2]. About 75% of trisomy 21 fetuses have increased nuchal translucency (NT) and 60–70% have absent nasal bone.

#### **2.1 History of screening methods**

Aneuploidy increases with advancing maternal age. So, increasing the maternal age increases the risk. in the early 1970s, the screening was based only on the association with advanced maternal age. In late 1980s not only maternal age but also found that the concentration of various fetoplacental products in the maternal circulation has taken into account for screening. At 16 weeks of gestation the median maternal serum concentrations of alpha-fetoprotein (AFP), un-conjugated estriol (μE3), human chorionic gonadotropin (HCG) (free- β and total**)** and inhibin-A in aneuploidy are sufficiently different from normal to allow the use of combinations or some or all of these substances to select high risk group. This method is more effective than maternal age alone. It can identify about 60–70% of the fetuses with T21. In1990s, screening by a combination of maternal age and fetal NT thickness at 11–13 + 6 weeks of gestation was introduced. This method shown to identify about 75–80% of affected fetuses for a screen-positive rate of about 5%. There by,

**Figure 1.** *Aneuploidy screening Approach: observed Detection rates.*

#### *Prenatal Screening of Aneuploidies DOI: http://dx.doi.org/10.5772/intechopen.96757*

maternal age was combined with fetal NT and maternal serum biochemistry (free β-HCG and PAPP-A) in the first-trimester to identify about 85–90% of affected fetuses. In 2001, it was found that 60–70% Trisomy 21 fetuses were associated with non-visualized nasal bone. Inclusion of nasal bone and the other ultrasound markers to NT and biochemistry for the screening procedure increase the detection rate in to more than 95% in first trimester with a screen positive rate of 2.5% (**Figure 1**). Furthermore, introduction of one-stop clinics for assessment of risk (OSCAR) which is a new method of biochemical testing, where with-in 30 min of taking blood sample, made it possible to assess the risk [3, 4].

#### **3. Type of screening tests**

"Down syndrome" can be diagnosed during pregnancy. Diagnostic tests are invasive and have an inherent miscarriage rate, however, small they are also expensive. Screening tests can identify a large number of patients who would benefit from diagnostic testing thus reducing risks and costs. Screening tests by definition, cannot identify all accepted pregnancies. First trimester screening is far more effective than later screening. Aneuploidy screening should be offered to all the pregnant women.

Screening tests that are performed in the first and second trimesters include integrated, sequential and contingent screening. The basic types are 1) first trimester combined screening the components in this are Nuchal translucency (NT), PAPP-A and β-HCG. The detection rate is 85–95%. If you add nasal bone and other ultrasound features to this the detection rate increases 93–96%. 2) Triple test the components are β-HCG, MS-AFP and unconjugated Estriol. The detection rate is only 60–65%. 3) Quadruple test β-HCG, MS-AFP, unconjugated Estriol and inhibin A. the detection rate is 70–75%. 4) Penta screen includes hyper glycosylated HCG in addition to quadruple test. If patient come for screening in first trimester, first trimester combined screening is advised, if she comes at 14-20 weeks quadruple test, if she comes at both first and second trimester integrated test is best for screening (**Table 1**).

Integrated test:-Integrate the First trimester PAPP-A, Free β-HCG and NT analyte screening followed by a second trimmester Quad screen and receives a single


#### **Table 1.**

*Methods of screening and its detection rate.*

screen test result. The detection rate of this test is 90–94%. Limitations includes the withholding of first trimester screening test results until the second trimester which delay the management option.

Sequential screening: - these are two types one is stepwise another one is contingent model. These methods were developed to maintain a high detection rate. in step wise sequential model it can be achieved by using the combined first and second trimester screening approach while also reporting the patients first trimester screening test risk, which allows for earlier management options. If first trimester test result is higher than lab derived positive screening cutoff, we can offer them the diagnostic test or NIPT, and the screening protocol is discontinued. If the patient has a lower risk can counseled and proceed to quad screening in the second trimester. Sequential screening has a detection rate of 91–93% with a positive screening test result rate of 4–5% [5–7].

Contingent model classifies aneuploidy risk as high, intermediate or low on the basis of first trimester screening test results. High risk patients are offered cell free DNA screening or diagnostic testing with CVS and for low risk women further screening or testing is not recommended. Only those with intermediate risk are offered second trimester screening.

#### **4. Method of sequential screening**

Every woman has a risk that her fetus has a chromosomal abnormality.

#### **4.1 Standard first trimester aneuploidy screening**

to calculate the individual risk, the clinical information which is necessary to take into account the background or a priori risk, depends on maternal age, weight the ethnicity (in terms of south Asian, east Asian, south east Asian black or Caucasian), IVF, number of fetuses diabetes and smoking. This information should be combined with ultrasound information and biochemistry. Which is based on crown rump length, NT, PAPP-A, free β-HCG. Then make calculation by a series of factors or likelihood ratios, which depend on the results of a series of screening tests carried out during the course of the pregnancy to determine the patient-specific risk. A priori risk established by maternal age has been adjusted successfully by NT screening. This has been one of the most important elements of aneuploidy screening as it resulted in a significant reduction in unnecessary invasive testing on pregnant women with advanced maternal age. If you add rest of the ultrasound features like nasal bone, ductus venosus and tricuspid regurgitation which can increase the rate of detection.

#### **4.2 Standard genetic sonogram aneuploidy screening**

Genetic sonogram has been used to screen for Aneuploidy by using specific findings. In this approach seeks major structural abnormalities and minor ultrasonographic soft markers. These Soft markers are minor ultrasound abnormalities, considered as variants of normal, they do not constitute a structural defect. Presence of Soft markers are indicative of an increased age adjusted risk of an underlying fetal aneuploidy or some non- chromosomal abnormalities. So, these are also a priori risk. Detection of soft markers increase the risk for aneuploidy by constant proportion (likelihood ratio LR). Absence of these markers lower the risk (Negative predictive value NPV). These were decided after a meta-analysis study of second trimester markers for trisomy21 [8], (**Table 2**).

#### *Prenatal Screening of Aneuploidies DOI: http://dx.doi.org/10.5772/intechopen.96757*


#### **Table 2.**

*Meta-analysis of 2nd trimester markers for trisomy21-M. Agathokleous et al.*

Every time a test is carried out the *a priori*risk is multiplied by *the likelihood ratio* of the test to calculate a new risk, which then becomes the *a priori*risk for the next test [9].

If a systematic second- trimester ultrasound examination demonstrates the absence of all major defects and markers, there is a 7.7fold reduction in risk for trisomy 21. Detection of any one of the markers during the scan should stimulate the sonographer to look for all other markers or defects. Post-test odds for trisomy 21 is derived by multiplying the pre-test odds by the positive LR for each detected marker and the negative LR for each marker demonstrated to be absent.

In Sequenitial screening first do the first trimester combined screening test identify the risk based on this risk if it is high risk do the invasive procedure (CVS) or NIPT. If there is false positive and false negetive results then you need to combine with quadraple test and sequentially calcuate the risk as the false positive rate is very very low.

#### **5. Biochemical markers**

First trimester markers are pregnancy associated plasma protein A (PAPP-A), Free β Human chorianic gonadotropin (β-HCG) where as second trimester markers are Alpha fetoprotein (AFP) Unconjugated oestriol (μE3), Total human chorianic gonadotropin (HCG) and inhibin-A.

The PAPP-A level is low in T21 which is about half of euploid pregnancies. β-HCG levels are double that of unaffected pregnancies. The concentrations of these markers vary with gestational age. In first trimester PAPP-A increases and free β-HCG decreases. In second trimester AFP and μE3 increase HCG and inhibin-A will decreases before 17 weeks after that it may increas. The measurements of these markers may vary between laboratories. In account of this variation the concentration of each marker is expressed as multiple of median for unaffected pregnancies of the same gestational age (MoM).

#### **6. First trimester sonographic markers**

provision of a high-quality first trimester screening service significantly enhances the autonomy of pregnant women [10].

#### **6.1 Nuchal translucency (NT)**

The gestation should be 11–13 + 6 weeks and the fetal crown–rump length should be 45–84 mm. Criteria for the Standardized Measurement of the Nuchal translucency at 11–13 + 6 weeks are- fetus must be in the midsagittal plane. The image must be magnified so, that it is filled by the fetal head, neck and upper thorax, the magnification should be as large as possible and each slight movement of the callipers should produce only a 0.1 mm change in the measurement. The fetal neck must be in neutral position, it should not be flexed, and not hyperextended. Amnion must be seen separate from NT line. The margins of NT edges must be clear enough for proper placement of the callipers (**Figure 2**). The + callipers on the ultrasound must be used to perform the NT measurement. Electronic callipers must be placed on the inner borders of the nuchal line space with none of the horizontal crossbar itself protruding into the space and the callipers must be placed perpendicular to the fetal long axis. Measurement must be obtained at the widest space of the NT. Cord round the neck may be present in 5–10% of cases which may produce a falsely increased NT. In such cases, the measurements of NT above and below the cord are different so, the average of these two measurements should be appropriate for calculating risk. One of the studies involving 96,127 pregnancies, at a crown rump length of 45 mm the median and 95th centile was 1.2 and 2.1 mm and the crown rump length of 84 mm were 1.9 and 2.7 mm [11]. The average NT in aneuploidy is about 2.5 mm above the normal median for crown-rump length. In Turner syndrome, the median NT is about 8 mm above the normal median.

#### **6.2 Nasal bone (NB)**

It may be present, absent or hypoplastic. In the normal fetus between the 11th and early 12th week of gestation, the nasal bone may appear poorly ossified or absent [12]. In such cases, it is recommended to repeat the measurement one week later [12]. Nasal bone hypoplasia is calculated as BPD/NBL ratio if >11 than hypoplasia. Several studies have demonstrated a high association between absent nasal bone at 11–13 + 6 weeks and trisomy 21, as well as other chromosomal abnormalities [13]. Criteria for the Standardized Measurement of the Nasal Bone at 11– 13 + 6 weeks are mid sagittal view of face with the magnification of the image should be such that the fetal head and thorax occupy the whole screen. Mid sagittal face is defined by the presence of the echogenic tip of the nose and rectangular

**Figure 2.** *Normal NT and nasal bone.*

*Prenatal Screening of Aneuploidies DOI: http://dx.doi.org/10.5772/intechopen.96757*

shape of the palate anteriorly, the translucent diencephalon in the center, and the nuchal membrane posteriorly. Minor deviations may cause non-visualization of the tip of the nose and visibility of the zygomatic process of the maxilla. The ultrasound transducer should be parallel to the direction of the nose and it should be gently tilted from side to side to ensure that the Nasal bone is seen separate from the skin (**Figure 2**). The echogenicity of NB should be greater than the overlying skin. Three distinct lines are noted in nasal bone demonstration: the first two lines are horizontal and parallel to each other where the top line represents the skin and bottom line is the NB. Third one represents the tip of the nose. When the NB line appears as a thin and less echogenic than the overlying skin, which suggests that the NB is not yet ossified, and it is classified as being absent (**Figure 5**) [12].

#### **6.3 Ductus venosus (DV)**

Criteria for the Standardized Measurement of DV at 11–13 + 6 weeks are the magnification of the image should be such that the fetal head and thorax should occupy the whole screen. Right ventral mid sagittal view of fetal trunk should be obtained. Color flow mapping of umbilical vein DV and fetal heart should be

**Figure 3.** *Normal ductus venosus.*

**Figure 4.** *Normal tricuspid valve.*

demonstrated. Pulse doppler sample volume should be small (0.5–1.0 mm) and it should be placed in the yellowish aliasing area. Insonation angle should be less than 30degrees [12]. The filter should be set at a low frequency (50-70 Hz). Sweep speed should be high (2-3 cm/s) so that the waveforms are spread allowing better assessment of the A wave (**Figure 3**). Ductus venosus shows biphasic wave form with low pulsatility and antegrade flow in the diastolic components (a wave) throughout cardiac cycle. Normal ductus venosus Doppler waveforms show a positive a-wave, whereas the presence of an absent or reversed a-wave defines abnormal ductus venosus waveforms. The presence of high pulsatility or reverse flow of the a-wave in the first trimester increases the risk for chromosomal anomalies, cardiac defects, and the occurrence of twin-twin transfusion syndrome in monochorianic twins. Abnormal flow in the ductus venosus in about 80% of trisomy 21 fetuses and in about 5% of chromosomally normal fetuses [13].

#### **6.4 Tricuspid Valve**

Color and pulsed Doppler examination across the tricuspid valve is commonly used in the first trimester to assess for the presence of tricuspid valve regurgitation (TR). The presence of TR in the first trimester has been associated with chromosomal abnormalities [14, 15]. In the first trimester, TR is found in less than 5% of chromosomally normal fetuses, in more than 65% of fetuses with trisomy 21, and in more than 30% of fetuses with trisomy 18 [14]. Interrogation of other cardiac valves with color or pulsed Doppler is reserved for fetuses at risk for valve obstruction or when a cardiac malformation is suspected. Criteria for tricuspid valve evaluation at 11–13 + 6 weeks are- image should be such that the fetal thorax occupies most of the image (**Figure 4**). heart should be in apical position. Sample volume should be 2-3 mm should be positioned across the tricuspid valve with an angle should be less than 30 degrees from the direction of the interventricular septum. Significant TR is

#### *Prenatal Screening of Aneuploidies DOI: http://dx.doi.org/10.5772/intechopen.96757*

defined when regurgitation is more than half of the systole with velocity of >60 cm/s. The sweep speed should be 2-3 cm/s so that the wave forms are widely spread for better assessment. The tricuspid valve could be in sufficient in one or more of its three cusps, so, therefore the sample volume should be placed across the valve at least three times in an attempt to interrogate the complete valve [12].

#### **6.5 Hepatic artery**

It has been reported that high peak velocities in the hepatic artery are present in the first trimester in fetuses at risk for trisomy 21.

#### **7. Second trimester soft markers**

They are absent nasal bone, Aberrant subclavian artery, ventriculomegaly, increased Nuchal fold, Echogenic bowel loops, mild hydronephrosis, echogenic intra cardiac foci, short femur short humerus, choroid plexus cysts, single umbilical artery.

Major or minor abnormalities are found in about 75% of fetuses with trisomy 21 and in 10–15% of chromosomally normal fetuses. The Genetic sonogram is a targeted ultrasound looking for major abnormalities as well as minor markers for aneuploidy. Over the years these minor markers are being looked into and things like widened pelvic angle sandal gap deformity is going out of favour and is getting replaced by ARSA, pre nasal thickness and FMF angle. Absence of these markers decreases the risk of downs by around 70–80% but does not completely rule out Downs and hence Absence gives additional reassurance to the patient.

In first step when a soft marker is identified thoroughly search for other soft markers and structural abnormalities. In second step calculate the risk of aneuploidy based on likelihood ratios. This risk is calculated against background risk based maternal age alone or in combination with First trimester combined screening or second trimester quadruple test.

#### **7.1 Increased nuchal fold**

In second and third trimesters of pregnancy, abnormal accumulation of fluid behind the fetal neck can be known as nuchal cystic hygroma or nuchal edema. In about 75% of fetuses with cystic hygroma, there is a chromosomal abnormality and, in about 95% of cases, the abnormality is Turner syndrome. Chromosomal abnormalities are found in about one-third of the fetuses of nuchal edema and, in about 75% of cases, the abnormality is trisomy 21 or 18. Edema is also associated with fetal cardiovascular and pulmonary defects, skeletal dysplasia, congenital infections and metabolic and haematological disorders; The positive LR is 23.3 and negative LR is 0.8. Nuchal index is considered by some, because this is associated with gestational age. Nuchal index is (mean nuchal fold/mean BPD) x100 where the value of 11 or greater has a sensitivity of 50% and specificity of 96% (**Figure 6**).

#### **7.2 Aberrant right subclavian artery (ARSA)**

occurs in 0.5to 1.4%. four vessels arise from the aortic arch where the right subclavian artery arises from distal part of the aortic arch and courses behind the oesophagus and trachea to the right upper arm (**Figure 7**). ARSA is present in 1% of euploid fetuses and 24% of trisomy 21. ARSA is associated with other conotruncal

**Figure 6.** *Nuchal oedema.*

anomalies increases the risk of microdeletion 22Q11 and other syndromes. The positive LR is 21.5 and negative LR is 0.71. when it is isolated LR is 3.9 times.

#### **7.3 Echogenic bowel loop**

This may be due to Swallowed blood, Cystic fibrosis or maternal infections. It may be also associated with congenital malformations of the bowel more so of upper GI lesions. And other perinatal complications, including fetal growth restriction. We have to also look for Ascites and bowel dilatation. Diagnosis of echogenic bowel should be confirmed by low frequency transducer, reduced Gain and without use of harmonics. Echogenicity should be equal to or more than bone (**Figure 8**). Grade 2 similar to bone echogenicity Grade 3 is more than bone. The positive LR of this is 11.4 and negative LR is 0.9.

*Prenatal Screening of Aneuploidies DOI: http://dx.doi.org/10.5772/intechopen.96757*

**Figure 8.** *Echogenic bowel loops.*

#### **7.4 Short femur/short Humerus**

Short Femur and humerus is when the measurement is below 5th percentile for gestational age or measured/expected ratio < 0.9. The positive LR is 3.72 and negative LR is 0.8. regarding short humerus is the humerus measuring <2.5% or measured/expected ratio < 0.89. The Positive LR is 4.81 and negative LR is 0.74.

#### **7.5 Echogenic intracardiac focus (EICF)**

usually noted at region of papillary muscle 88% in Lt ventricle, 5%in rt. ventricle and 7% in biventricular. The echogenicity should be comparable to bone. Grading of EICF - Grade 2 similar echogenicity of bone and grade 3 more denser than bone (**Figure 9**). EICF in RV, biventricular, multiple and bright EICF are more associated

with aneuploidy, when compared to solitary LV EICF. The positive LR is 5.83 and negative LR is 0.8.

#### **7.6 Mild ventriculomegaly**

Normal ventricular measurements are <10 mm. If it is defined as mild ventriculomegaly when measurement is between 10 and 15 mm. (**Figure 10**). The overall prevalence of chromosomal defects in fetal ventriculomegaly is about 10% and the commonest chromosomal defects are trisomies 21, 18, 13 and triploidy. The positive LR is 27.52and negative LR is0.94.

**Figure 10.** *Mild ventriculomegaly.*

#### **7.7 Mild hydronephrosis**

pelvic AP diameter measuring >4 mm and it should be measured in transverse section in 12 clock or 6 clock position. The positive LR is 7.6 and negative LR is 0.92 (**Figure 11**).

There are other soft markers also those doesn't have any likely hood ratio but they are important and common in our practise but they are not a part of screening

*Prenatal Screening of Aneuploidies DOI: http://dx.doi.org/10.5772/intechopen.96757*

**Figure 12.** *Small membranous VSD.*

protocol. They are the choroid plexus cysts and single umbilical artery, sandal gap toes, short ears, clinodactyly, increased iliac angle. Not only this Duodenal atresia and small membranous VSD (**Figure 12**) is also be associated with aneuploidy [16].

#### **7.8 Choroid plexus cysts**

they may be round or oval. May be unilateral or bilateral. They may be large or small. Commonly seen between 16 and 21 weeks by 23 week start undergoing regression. After 25–26 weeks uncommon to see. More commonly associated with trisomy 18. LR for trisomy 18 when isolated is 1.1–1.5.

#### **7.9 Single umbilical artery**

No strong association with aneuploidy. Usually associated with fetal cardiac, renal anomalies and oesophageal atresia (**Figure 13**).

**Figure 13.** *Single umbilical artery.*

#### **7.10 Pre nasal thickness**

In normal fetuses, the pre nasal thickness is small and the nasal bone is relatively long, resulting in a ratio of approximately 0.6 [17]. In trisomy 21 fetuses in the first trimester, the prenasal thickness increases, whereas the nasal bone length decreases, resulting in a ratio > 0.8 [17].

#### **8. Non-invasive prenatal testing (NIPT)**

Other names for NIPT are NIPS- non-invasive prenatal screening, cfDNA- cell free DNA. The test is based upon the presence of fetal cell-free DNA in the maternal circulation. Placental cell apoptosis releases into the maternal circulation as small DNA fragments (150-200 bp) that can be detected from >7 weeks of gestation [18]. It is estimated that about 2–20% of circulating cfDNA in the maternal circulation is fetal in origin [18]. So, about 1 in 103 –107 nucleated cells in maternal blood are fetal which can be enriched to about 1in 10–100 by techniques such as magnetic cell sorting (MACS) or fluorescence activated cell sorting (FACS) after attachment of magnetically labelled or fluorescent antibodies on to specific fetal cell surface markers. However, with the use of fluorescent *in situ* hybridization (FISH) and chromosome specific DNA probes it is possible to suspect fetal trisomy by the presence of threesignal nuclei in some of the cells of the maternal blood enriched for fetal cells. On the basis of currently available technology, examination of fetal cells from maternal blood is more likely to find an application as a method for assessment of risk. The sensitivity of NIPT is comparable to serum screening. Analysis of fetal cells from maternal blood is both labour intensive and requires highly skilled operators whereas in biochemical screening which is relatively easy to apply for mass population screening. The halflife of cfDNA is short and is typically undetectable within hours after delivery [19]. the detection rate for T21 is at 99% for a false-positive rate of 0.16% [20, 21]. Detection rate for T18 is at 97% for a false-positive rate of 0.15% [20]. The use of NIPT is rapidly expanding and is now being offered as the primary screening test in pregnancy. Even if the NIPT test has an excellent detection rate for T21, T18, and T13, other aneuploidies remain missed [22–24]. NIPT is a screening and not a diagnostic test so, caution should be used when NIPT is incorporated in the genetic evaluation of fetal malformations. Low fetal fraction is noted in High body mass and sampling before 10 weeks of gestation.in some laboratories fetal fraction <4% are considered too low to report a result which is often referred as a "no call "result. NIPT results depends on duration of gestation, number of fetuses and whether the fetus is live or not. For confirming number, gestational age and viability needs ultrasound examination before going for NIPT. If its low-risk population the positive predictive value of NIPT is low. False positive in NIPT are in placental mosaicism, vanishing Twin, maternal sex chromosome abnormality and Neoplasia. Even if NIPT is true positive it can-not distinguishes aneuploidy derived from translocation or disjunction type which is needed to know the recurrence risk for this again needs diagnostic test. Not only this the women who has no call report result needs comprehensive ultrasound evaluation and diagnostic tests because low fetal fraction may be associated with increased risk of aneuploidy.

#### **9. Invasive fetal testing**

1) **Chorionic villous sampling** should be done at 10–15 weeks. and overall fetal loss is 1%. This test can be done trans abdominal/trans vaginal approach and this

#### *Prenatal Screening of Aneuploidies DOI: http://dx.doi.org/10.5772/intechopen.96757*

procedure should be done under ultrasound guidance and the sample is Trophoblast cells. Result comes within 48–72 hrs. Randomized studies have demonstrated that the rate of fetal loss following first-trimester transabdominal chorionic villus sampling is the same as with second-trimester amniocentesis. There is an association between chorionic villus sampling before 10 weeks to fetal transverse limb abnormalities, micrognathia and microglossia. It is therefore imperative that chorionic villus sampling is performed only after 11 weeks by appropriately trained operators.

2) **Amniocentesis** should be done at 15–20 weeks. In this we introduce needle inside the amniotic cavity to extract the amniotic fluid. Sampling cells are amniocytes, fetal dermal fibroblasts. Karyotype results take 7–10 days, and overall fetal loss is 0.5%.

3) **cordocentesis** (per cutaneous umbilical blood sampling) which should be done at >18-20 weeks. Under ultrasound guidance needle should be introduced into the cord near the placental insertion. Sampling should be done from umbilical vein. Sampling cells are fetal blood cells sampled from umbilical vein and overall fetal loss is 1.5–3%. In a randomized study, 4,606 low-risk, healthy women, 25–34 years old, at 14–20 weeks of gestation, were randomly allocated to amniocentesis or ultrasound examination alone [25]. The total fetal loss rate in the patients having amniocentesis was 1% higher than in the controls. The study also reported that amniocentesis was associated with an increased risk of respiratory distress syndrome and pneumonia. Randomized studies have demonstrated that after early amniocentesis i.e., around 10–14 weeks of gestation the rate of fetal loss is about 2% higher and the incidence of talipes equinovarus is 1.6% higher than the firsttrimester chorionic villus sampling or second-trimester amniocentesis. It was apparent that amniocentesis carried a risk of miscarriage and this in conjunction with the financial cost implications, meant that prenatal diagnosis could not be offered to the entire pregnant population.

#### **10. Sonographic and biochemical features of Aneuploidy**

#### **10.1 Trisomy 21**

Factors that is associated with an increased risk of "Down syndrome" are higher maternal age, a parental translocation involving chromosome 21, previous child with T21, significant ultrasound findings and a positive screening test result. In pregnancies with T21 fetuses, the maternal serum concentration of free β-HCG is about twice (about 2MoM) as high and PAPP-A is reduced to half (about 0.5 MoM) compared to euploid pregnancies. Although NT measurement alone identifies about 75–80% of T21 fetuses, the combination of NT with maternal biomarkers in the first trimester increases the T21 detection rate to 85–95%, while keeping the falsepositive rate at 5%. AFP is decreased in T21.

In addition to NT, other sensitive first trimester ultrasound markers of T21 include absence or hypoplasia of the nasal bone (60–70%), increased impedance to flow in the ductus venosus (about 80%), tricuspid regurgitation, cardiac malformations (atrioventricular septal defect) with or without generalized edema, aberrant right subclavian artery and echogenic intracardiac focus. Increased fronto maxillary fascial angle (short maxilla in 25%), renal pylectasis and echogenic bowel loops are also soft markers for "Down syndrome" (**Table 3**) (**Figures 14**–**18**).

In second trimester scan the soft markers in Trisomy 21 are nasal hypoplasia, increased nuchal fold thickness, intracardiac echogenic foci, echogenic bowel, hydronephrosis, shortening of the femur and more so of the humerus. It may also be


#### *Down Syndrome and Other Chromosome Abnormalities*

#### **Table 3.**

*Common chromosomal defects in fetuses with sonographic abnormalities [9, 26].*

*T21 Fetus of 12 weeks 3 days showing normal NT with AFNB and Tricuspid regurgitation.*

associate with cardiac defects, duodenal atresia, sandal gap and clinodactyly or midphalanx hypoplasia of the fifth finger. Trisomy 21 is found in about 40% of cases of duodenal atresia.

**Figure 15.** *T21 fetus of 13 weeks 5 days showing increased NT with Omphalocele.*

**Figure 16.**

*T21 fetus showing Increased NT with dilated posterior fossa and reverse flow in ductus venosus.*

**Figure 17.** *T21 with Atrioventricular septal defect with duodenal atresia(double bubble sign) and cleft lip with palate.*

**Figure 18.** *T21 with Absent nasal bone with EIC, ARSA and club foot.*

#### **10.2 Trisomy 18 and Trisomy13**

Thickened NT is a common first trimester findings in Aneuploidy. In T18 and T13, NT median values were shown to be 5.5 and 4.0 mm, respectively [16, 27]. Reduced PAPP-A value in both trisomies noted with a median value of 0.2 MoM for T18 and 0.3 MoM for T13. Free β-HCG values are decreased whereas it is increased in T21. In T18 and T13 median values of free β-HCG 0.2 MoM and 0.5 MoM, respectively. T18 or T13 is often first suspected by the presence of typical ultrasound features, rather than by biochemical screening (**Figures 19**–**25**). single umbilical artery is found 80% fetuses with T18 and in about 3% of chromosomally normal fetuses [28]. There is 7fold increased risk of T18 associated with single umbilical artery noted. Presence of megacystis After taking into account maternal age and fetal NT the increases the likelihood for trisomy 13 or 18 by a factor of 6.7.

Presence of exomphalos in association with T18 in first trimester is 60% compared about 30% at mid gestation and 15% in neonates. Trisomy 13 and Turner syndrome are associated with tachycardia, whereas in trisomy 18 and triploidy there is fetal bradycardia [29]. pulsatile flow in the umbilical vein is noted in 90% of fetuses in T18 and T13 where as 25% of chromosomally normal fetuses. The prevalence of chromosomal defects in Dandy walker -complex is about 40%, mainly in trisomies 18, 13 and triploidy.

#### **Figure 19.**

*T18 12 weeks 1 day showing increased NT, absent nasal bone, cleft lip and palate and Congenital talipes equinovarus.*

**Figure 20.** *T18 fetus of 15 weeks gestational age with Holoprocencephaly and radial ray abnormality.*

#### **Figure 21.**

*T18 fetus showing normal NT with dilated posterior fossa and single umbilical artery at 13 weeks 2 days followup 3D at 16 weeks 4 days with vermian rotation and incread Brainstem vermian angle.*

#### **Figure 22.**

*Fetus of T18 showing Diaphragmatic hernia, choroid plexus cysts and bilateral rocker bottom foot at 21 weeks 5 days gestation.*

#### **Figure 23.**

*15 weeks 5 days fetus of T13 showing holoprocencephaly, club hands and aborted fetus showing midline cleft with proboscis anophthalmia and bilateral club hands.*

**Figure 24.** *Megacystits with increased NT of 12 weeks 1 day T13 fetus.*

#### **Figure 25.**

*15 weeks 3 days fetus showing micrognathia with polydactyly and syndactyly. In another fetus of 14 weeks 2 days 3D showing increased NT with posterior fossa dilatation and micrognathia in T13 cases.*

20% 0f diaphragmatic hernia is associated with chromosomal defects mainly withTrisomy18. Heart abnormalities are found in more than 90% of fetuses with trisomy 18 or 13 and 40% of those with trisomy 21 or Turner syndrome. 30% and 15%

#### *Prenatal Screening of Aneuploidies DOI: http://dx.doi.org/10.5772/intechopen.96757*

cases of Exomphalos at mid gestation and in neonates are associated with Chromosomal defects, mainly trisomies 18 and 13. The prevalence of chromosomal defects is four-times higher when the exomphalos sac contains only bowel than in cases where the liver is included. Prenatally 20% of oesophageal atresia cases are associated with chromosomal defects, mainly trisomy 18. Polydactyly is associated with trisomy 13, overlapping fingers, Talipes and rocker bottom feet are associated with trisomy 18. Usually, Trisomy 18 and triploidy are associated with moderately severe growth restriction whereas trisomy 13, Turner syndrome with mild growth restriction and in trisomy 21 growth is essentially normal [30]. In second trimester scan Trisomy 18 is associated with strawberry-shaped head, choroid plexus cysts, absent corpus callosum, enlarged cisterna magna, facial cleft, micrognathia, nuchal edema, heart defects, esophageal atresia, diaphragmatic hernia and usually exomphalos with bowel only in the sac. The other associated findings are single umbilical artery, renal abnormalities, echogenic bowel, myelomeningocele, growth restriction and shortening of the limbs, radial aplasia, overlapping fingers and talipes or rocker bottom feet.

Trisomy 13 is associated with microcephaly, holoprosencephaly, facial abnormalities, cardiac abnormalities, exomphalos, enlarged and echogenic kidneys and post axial polydactyly.

#### **11. Monosomy X (turner syndrome)**

NT has a median value of 7.8 mm [16] and has often been described as a cystic hygroma (**Figure 26**). The occurrence of monosomy X is not related to maternal age. Typically, lymphatic disturbances in turner syndrome are not limited to the neck region but involve the whole body including the presence of skin edema, hydrothorax and ascites. Generally Normal Nasal bone is present in fetuses with monosomy X [31]. Normal maternal serum-free β-HCG (1.1 MoM) and low PAPP-A is noted (0.49 MoM) [32]. Typical sonographic features in monosomy X includes large nuchal cystic hygromas, generalised edema, mild pleural effusions and ascites, cardiac abnormalities like left ventricular outflow tract obstruction, fetal tachycardia and renal anomalies such as the presence of horseshoe kidneys.

**Figure 26.** *2 different cases of turners syndrome with generalised edema and cystic hygroma.*

### **11.1 Triploidy**

In triploidy, there is a complete additional haploid set of chromosomes resulting in 69 chromosomes in each cell instead of 46 chromosomes. The additional haploid set can be of paternal or maternal origin. The "paternal" type is called diandric triploidy and the "maternal" type is called digynic triploidy. These two types show different features, which can be often differentiated on ultrasound. The typical pattern of diandric triploidy includes the presence of a normally grown fetus with molar placenta, whereas in digynic triploidy, severe growth restriction is noted with a small but not molar placenta. Profile of biochemistry is different in both types due to these placental differences. Diandric triploidy is associated with increased maternal serum-free β-HCG and mildly decreased PAPP-A and in digynic triploidy which is associated with markedly decreased maternal serum free β-HCG and PAPP-A. Significantly short CRL with marked difference in size between the abdominal and head circumference, typically of more than 2 weeks of gestational age [33] which is a pathognomonic sign of digynic triploidy (**Figure 27**). In second trimester scan Triploidy where the extra set of chromosomes is paternally derived is associated with a molar placenta and the pregnancy rarely persists beyond 20 weeks. When there is a double maternal chromosome contribution, the pregnancy may persist into the third trimester (**Figure 27**). Commonly there is mild

#### **Figure 27.**

*Two fetuses of Digynic Triploidy showing short CRL with size difference in abdominal head circumference.*

ventriculomegaly, micrognathia, cardiac abnormalities, myelomeningocele, syndactyly, and 'hitch-hiker' toe deformity (**Figure 28**).

#### **12. Risk assessment in first and second trimester**

The risk for trisomies in women who have had a previous fetus or child with a trisomy is higher than the one expected on the basis of their age alone.

when we have only CRL, NT, maternal age without biochemical markers there are calculators where we can enter these measurements, we get the risk assessment for downs at the time of birth- Pregnancy calculators- EDD. We can do same thing with only 2nd trimester markers without biochemical or first trimester screen results for this we will take the LR+ value of each marker present and LR- values of all absent markers and multiple all of these to get the LR for combination [8].

Instead if we find any soft markers we enter the same into the excel sheet provided by [8] M. Agathokleous et al. Excel sheet for downs.

Meta- analysis of second-trimester markers for trisomy21 [8] M. Agathokleous et al., ultrasound obstet Gynecol 2013;41:247–261.

For example:-.

when we get the measurements, we apply the same into the calculators and get the risk assessment for downs at the time of birth. It is given as in 1 in —————.

>1in 19(high risk): offer invasive testing.

>1in 50(high risk): offer NIPT/Invasive testing.

<1in 1000(Low risk): Back to routine second trimester genetic sonogram.

1in 50-1in 999(intermediate risk): Assess NB, DV, TR and recalculate risk+/-NIPT. New cut-of risk for downs as 1:250, borderline between 251 and 1000, and less risk if <1:1001.

First trimester between 11 and 13 weeks 6 days scan evaluate NT, nasal bone along with Tricuspid valve regurgitation, a wave in Ductus Venosus and other major structural defects. Not only this detail cardiac evaluation should be done. If there is no abnormality repeat scan at 18–22 weeks may be recommended. In the second trimester scan look for soft markers, if there is any marker or abnormality detailed anatomy scan and echocardiography. In case of most isolated markers including intra cardiac echogenic focus, echogenic Bowel, mild hydronephrosis and short femur, there is only a small effect on modifying the pre-test odds.

All these are only screening protocols they are not diagnostic so, fetal karyotyping option is aways open to either risk groups.

Previous affected Pregnancy.

In women who had a previous pregnancy with trisomy 21, the risk of recurrence in the subsequent pregnancy is 0.75% higher than the maternal and gestational agerelated risk for trisomy 21 at the time of testing. Recurrence is chromosome specific. If a previous pregnancy is T21 the result will be classified as screen positive regardless of level of screening markers. Risk is calculated which takes account of a women's age at the time of her previous pregnancy with "Down syndrome" for the risk calculation.

"Down syndrome" may be non-disjunction type (95%) where there is a recurrence rate of 1% where as in translocation type like (21–21) if either parent is carrying same type of translocation then there is 100% rate of recurrence.

If there is h/o prior affected downs child screening test is not reassuring her so, better to go for direct invasive testing if she comes at first trimester go for CVS.

In Twin gestation.

Dichorionic twin- Free β-HCG and PAPP-A levels are nearly twice as high as singleton. Calculate the risk for each fetus based on maternal age and fetal NT. If one fetus the NT is increased look for other markers. Detection rate is 75–80%.

In monozygotic twins' risk is same as singleton pregnancies.

In monochorionic twin pregnancies raised NT is an early manifestation of TTTS. So, false positive rate will be increased. Free beta HCG and PAPP-A levels are lower than dichorionic twin to twin transfusion syndrome as well as for chromosomal abnormality.

Calculate the risk of each fetus based on NT, serum biochemistry and then the average risk between the two fetuses is considered as whole.

No method is accurate for screening of fetal aneuploidy as it is in singleton pregnancy.

Appropriate Models for aneuploidy detection:


#### **13. Conclusion**

In the economically privileged patient first trimester screening should include an 11–14 weeks complete assessment with first trimester combined screen, PIGF and NIPT. For population screening is by combined screening. Woman with positive screen test result should be counselled and offered the option of diagnostic testing. Those who have a negative test results should be counselled regarding their lower adjusted risk. Even if a woman has low risk results, she may choose diagnostic testing later in pregnancy whenever there is fetal anomalies or markers on followup sonography.

#### **Acknowledgements**

The authors wish to express thanks to all parentages involved for giving permission to collect the presented data. The authors also wish to express their thanks to Dr. Ashok Khurana, Dr. TLN Praveen and Dr. Krishna Gopal for the source of information.

*Prenatal Screening of Aneuploidies DOI: http://dx.doi.org/10.5772/intechopen.96757*

### **Author details**

Madhavilatha Routhu<sup>1</sup> \* and Shiva Surya Varalakshmi Koneru<sup>2</sup>


\*Address all correspondence to: madhaviradiologist@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 10**
