Inherited Bone Marrow Failure Syndromes

*Contemporary Pediatric Hematology and Oncology*

disrupted sleep in children with sickle cell disease. Sleep. 2011;**34**:899-908.

[59] Dhondt K, Baert E, Van Herzeele C,

fragmentation and increased periodic limb movements are more common in children with nocturnal enuresis. Acta Paediatrica. 2014;**103**:e268-e272. DOI:

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[62] Uwaezuoke SN, Eneh CI, Ndu IK. Nocturnal enuresis in children with sickle cell anemia: Global prevalence rates, gender bias and hypotheses on pathogenesis. Internal Medicine Review.

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[51] Li L, Zhou H, Yang X, Zhao L, Yu X. Relationships between 25 hydroxyvitamin D and nocturnal enuresis in five- to seven-year-old children. PLoS One. 2014;**9**:e99316. DOI: 10.1371/journal.pone.0099316

[52] Nolan VG, Nottage KA, Cole EW, Hankins JS, Gurney JG. Prevalence of vitamin D deficiency in sickle cell disease: A systematic review. PLoS One. 2015;**10**:e0119908. DOI: 10.1371/journal.

[53] Kheirandish-Gozal L, Peris E, Gozal D. Vitamin D levels and obstructive sleep apnoea in children. Sleep Medicine. 2014;**15**:459-463. DOI:

[54] Zicari AM, Occasi F, Di Mauro F, Lollobrigida V, Di Fraia M, et al. Mean platelet volume, vitamin D and C reactive protein levels in normal weight children with primary snoring and obstructive sleep apnea syndrome. PLoS One. 2016;**11**:e0152497. DOI: 10.1371/

[55] McCarty DE, Chesson AL Jr, Jain SK, Marino AA. The link between vitamin D metabolism and sleep medicine. Sleep Medicine Reviews. 2014;**18**:311-319. DOI: 10.1016/j.

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[57] Rogers VE, Lewin DS, Winnie GB, Gieger-Brown J. Polysomnographic characteristics of a referred sample of children with sickle cell disease. Journal of Clinical Sleep Medicine.

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**22**

**25**

**Chapter 3**

*Zhan He Wu*

**Abstract**

Predisposition

studies of cancer and aging.

syndromes

**1. Introduction**

Inherited Bone Marrow Failure

Inherited bone marrow failure syndromes (IBMFS) and chromosome instability syndromes (CIS) are the most classic and representative genetic syndromes. They are classified as genetic rare diseases, typically with complex medical complications in the delay of mental and physical development. Commonly, these syndromes present with different degrees of dysmorphics; organs/systems dysfunction generally and these syndromes have higher risk of inherited solid cancer and leukemia predisposition due to the similar pathway of DNA defects. These syndromes are often hard to diagnose and they overlap with their phenotypes clinically. Very importantly cancers from the germ line mutation of these syndromes require different treatment strategies with the sporadic malignancies. The significance of recognition of such diseases is not only beneficial to patients phenotypically affected but also to individuals phenotypically unaffected and members/relatives of the family. Remarkable advances have been made in the definition and classification of these genetic syndromes. Identification of the IBMFS and CIS has led to important advances in the understanding of the genotypes, guiding the clinical practice of the phenotypes. Interestingly, such studies provided insights into the function of the various DNA repair pathways. Fanconi anemia studies are an example in IBMFS and CIS is named as the paradigm of the

**Keywords:** inherited bone marrow failure syndromes, chromosomal instability syndromes, genetic rare syndromes, cancer predisposition, cancer prone human

inherited conditions transmitted in autosomal recessive pattern [1, 2].

Bone marrow failure is the term for the activity or function in the bone marrow production of blood cells from the hematopoietic cells. Studies demonstrated that there are more than 80 causative genes identified from bone marrow failure disorders but still about 40% of the disease cause is unidentified.  They are classified as genetic rare diseases, typically with complex medical complications in the delay of mental and physical development. Commonly, these syndromes present with different degrees of dysmorphics; organs/systems dysfunction generally and these syndromes have higher risk of inherited solid cancer and leukemia predisposition due to the similar pathway of DNA defects. These syndromes are often hard to diagnose and they overlap with their phenotypes clinically. Very importantly cancers from the germ line mutation of these syndromes require different treatment strategies with the sporadic malignancies. The significance of recognition of such diseases is not only beneficial to patients phenotypically affected but also to individuals phenotypically unaffected and members/relatives of the family. Remarkable advances have been made in the definition and classification of these genetic syndromes. Identification of the IBMFS and CIS has led to important advances in the understanding of the genotypes, guiding the clinical practice of the phenotypes. Interestingly, such studies provided insights into the function of the various DNA repair pathways. Fanconi anemia studies are an example in IBMFS and CIS is named as the paradigm of the studies of cancer and aging.

 Introduction**

Bone marrow failure is the term for the activity or function in the bone marrow production of blood cells from the hematopoietic cells. Studies demonstrated that there are more than 80 causative genes identified from bone marrow failure disorders but still about 40% of the disease cause is unidentified. Bone marrow failure disorders are classified into idiopathic (acquired) and inherited-(IBMFS) due to the inherited conditions transmitted in autosomal recessive pattern [1, 2].

There are more than 30 different types of disorders, classified into inherited bone marrow failure syndromes. The common types are Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, Congenital amegakaryocytic thrombocytopenia, Severe congenital neutropenia and thrombocytopenia absent radii [3, 4].

There is another group of syndromes named as chromosomal instability syndromes (CIS), are also known as chromosomal breakage syndromes, typically transmitted in an autosomal recessive pattern of inheritance defined on the basis of cell culture in vitro. The affected individuals exhibit elevated rates of chromosomal breakage or instability, leading to chromosomal rearrangements. CIS often lead to an increased tendency to develop certain types of malignancies as well [5, 6]. Individuals with IBMFS and CIS are commonly in children and these disorders are often lethal.

Relatively high rates of some types of IBMFS and CIS can occur in certain ethnic groups. Diagnosis is usually complicated because the symptoms presented from individuals with IBMFS and CIS may be varied and are often very complex. So practically the differential diagnosis of these two groups of syndromes clinically can be very difficult because they share some characteristics of overlapping phenotypes.

Studies on IBMFS and CIS for better therapies have achieved exciting successes, not only beneficial to IBMFS and CIS studies self but also beneficial to other diseases. One of the IBMFS and CIS, Fanconi anemia, is the disease which achieved a success in stem cell transplantation used umbilical blood in 1988 [7]. This revolutionary treatment has been using as an effective therapy for many different types of diseases, commonly in malignancies in clinical application since then. Studies found that the majority of IBMFS and CIS are associated with cancers from the germ line mutation and such studies have explored many mysteries in cancer research. For example, Fanconi anemia is found to associate with many different types of cancers from those mutated genes [8].

Recent advances in molecular-based studies on the identification of responsible genes and defects in their pathways of IBMFS and CIS have provided more understanding in the pathophysiological mechanisms. Such advances also provided the link between IBMFS/CIS and some types of cancers in the genetic defective pathways. Results obtained from research showed that human cancer is caused of genetic and environmental factors and their interactions in general. Cancers fall into the genetic disease category due to two genetic factors: (1) acquired somatic mutations produced by genomic instability and (2) inherited gene mutations. The important difference between familial/inherited and sporadic cancer is due to the form of germ line mutation in a DNA caretaker gene facilitating the accumulation of oncogenic DNA changes, which can result in a high susceptibility to cancer. Both IBMFS and CIS have cancer predisposition commonly in AML and MDS, often diagnosed at a young age. These types of malignancies require different treatment strategies due to the underlying gene defects.

To increase the recognition of myeloid leukemia/MDS associated with inherited or germ line mutations, a major change has been made by adding the germ line mutation in the classification of myeloid neoplasms and acute leukemia in the new version of classification of tumors of the hematopoietic and lymphoid tissues published by the World Health organization (WHO) in 2016 including (1) myeloid neoplasms with germ line predisposition without a pre-existing disorder or organ dysfunction, (2) myeloid neoplasms with germ line predisposition and pre-existing platelet disorder and (3) myeloid neoplasms with germ line predisposition and other organ

**27**

**Table 1.**

*Inherited Bone Marrow Failure and Chromosome Instability Syndromes and their Cancer…*

dysfunction. Similarly, studies demonstrated that hereditary predisposition has a higher risk of development of acute lymphoblastic leukemia (ALL) as reported in

Recently, studies on genetic disease by the modern technologies, particularly by the next generation sequencing dramatically increased the understanding of the etiology and classification of IBMFS. So more and more mutated genes have been identified and these studies demonstrated that genomic instability, defects in DNA repair and telomere biology are the genetic causes. Such discoveries have provided insights into several biological pathways, correlation between phenotype and

In this chapter, the aim IS to review and discuss IBMFS and CIS, together with comparison of their phenotypes and genotypes. It is hoped that review will increase understanding in further translation of research to clinical practice, so as to raise awareness of these genetic-based diseases and the impact on patients' lives as well as

IBMFS are a heterogeneous group of complex genetic disorders characterized by bone marrow failure, commonly associated with one or more somatic abnormalities

The common and representative types of IBMFS are Fanconi anemia, Dyskeratosis congenita, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, Congenital Amegakaryocytic thrombocytopenia, Severe congenital neutropenia and thrombocytopenia absent radii. The phenotype and genotype of IBMFS and

Fanconi anemia (FA) is a hereditary disorder with defects in DNA repair and is usually inherited as an autosomal recessive trait but it can be X-linked (FA

> **Bone marrow failure**

FA AR/XLR Yes Yes Yes Yes 22 [10, 78]

SDS AR Yes Yes Yes Yes 1 [28, 29] DBA AD Yes Yes Yes Yes 11 [31, 32] SCN AD/AR Yes Yes ? Yes 5 [36, 38] CAMT AR Yes Yes ? Yes 1 [39, 40] TAR AR Yes Yes ? Yes 1 [41, 42] *FA, Fanconi anemia; DC, dyskeratosis congenita; SDS, Shwachman-Diamond syndrome; DBA, Diamond Blackfan anemia; CAMT, congenital amegakaryocytic thrombocytopenia; SCN, severecongenital neutropenia; AD, autosomal*

**Short telomeres** **Cancer risk**

Yes Yes Yes Yes 9 [26, 27]

**Identified gene numbers**

**References**

*DOI: http://dx.doi.org/10.5772/intechopen.81546*

genotype, and clinical therapeutically strategies.

and increased cancer risks in childhood but also in adulthood.

**abnormalities**

improvement of the therapies.

**2.1 Fanconi anemia**

**2. The common types of IBMFS**

their association are summarized in **Table 1**.

**Syndromes Inheritance Somatic**

XLR

*dominant; AR, autosomal recessive; XLR, X-linked recessive.*

*Common types of inherited bone marrow failure syndromes.*

DC AD/AR/

TP53 [9].

*Inherited Bone Marrow Failure and Chromosome Instability Syndromes and their Cancer… DOI: http://dx.doi.org/10.5772/intechopen.81546*

dysfunction. Similarly, studies demonstrated that hereditary predisposition has a higher risk of development of acute lymphoblastic leukemia (ALL) as reported in TP53 [9].

Recently, studies on genetic disease by the modern technologies, particularly by the next generation sequencing dramatically increased the understanding of the etiology and classification of IBMFS. So more and more mutated genes have been identified and these studies demonstrated that genomic instability, defects in DNA repair and telomere biology are the genetic causes. Such discoveries have provided insights into several biological pathways, correlation between phenotype and genotype, and clinical therapeutically strategies.

In this chapter, the aim IS to review and discuss IBMFS and CIS, together with comparison of their phenotypes and genotypes. It is hoped that review will increase understanding in further translation of research to clinical practice, so as to raise awareness of these genetic-based diseases and the impact on patients' lives as well as improvement of the therapies.

### **2. The common types of IBMFS**

IBMFS are a heterogeneous group of complex genetic disorders characterized by bone marrow failure, commonly associated with one or more somatic abnormalities and increased cancer risks in childhood but also in adulthood.

The common and representative types of IBMFS are Fanconi anemia, Dyskeratosis congenita, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, Congenital Amegakaryocytic thrombocytopenia, Severe congenital neutropenia and thrombocytopenia absent radii. The phenotype and genotype of IBMFS and their association are summarized in **Table 1**.

#### **2.1 Fanconi anemia**

*Contemporary Pediatric Hematology and Oncology*

thrombocytopenia absent radii [3, 4].

often lethal.

phenotypes.

from those mutated genes [8].

strategies due to the underlying gene defects.

There are more than 30 different types of disorders, classified into inherited bone marrow failure syndromes. The common types are Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, Congenital amegakaryocytic thrombocytopenia, Severe congenital neutropenia and

There is another group of syndromes named as chromosomal instability syndromes (CIS), are also known as chromosomal breakage syndromes, typically transmitted in an autosomal recessive pattern of inheritance defined on the basis of cell culture in vitro. The affected individuals exhibit elevated rates of chromosomal breakage or instability, leading to chromosomal rearrangements. CIS often lead to an increased tendency to develop certain types of malignancies as well [5, 6]. Individuals with IBMFS and CIS are commonly in children and these disorders are

Relatively high rates of some types of IBMFS and CIS can occur in certain ethnic groups. Diagnosis is usually complicated because the symptoms presented from individuals with IBMFS and CIS may be varied and are often very complex. So practically the differential diagnosis of these two groups of syndromes clinically can be very difficult because they share some characteristics of overlapping

Studies on IBMFS and CIS for better therapies have achieved exciting successes, not only beneficial to IBMFS and CIS studies self but also beneficial to other diseases. One of the IBMFS and CIS, Fanconi anemia, is the disease which achieved a success in stem cell transplantation used umbilical blood in 1988 [7]. This revolutionary treatment has been using as an effective therapy for many different types of diseases, commonly in malignancies in clinical application since then. Studies found that the majority of IBMFS and CIS are associated with cancers from the germ line mutation and such studies have explored many mysteries in cancer research. For example, Fanconi anemia is found to associate with many different types of cancers

Recent advances in molecular-based studies on the identification of responsible genes and defects in their pathways of IBMFS and CIS have provided more understanding in the pathophysiological mechanisms. Such advances also provided the link between IBMFS/CIS and some types of cancers in the genetic defective pathways. Results obtained from research showed that human cancer is caused of genetic and environmental factors and their interactions in general. Cancers fall into the genetic disease category due to two genetic factors: (1) acquired somatic mutations produced by genomic instability and (2) inherited gene mutations. The important difference between familial/inherited and sporadic cancer is due to the form of germ line mutation in a DNA caretaker gene facilitating the accumulation of oncogenic DNA changes, which can result in a high susceptibility to cancer. Both IBMFS and CIS have cancer predisposition commonly in AML and MDS, often diagnosed at a young age. These types of malignancies require different treatment

To increase the recognition of myeloid leukemia/MDS associated with inherited or germ line mutations, a major change has been made by adding the germ line mutation in the classification of myeloid neoplasms and acute leukemia in the new version of classification of tumors of the hematopoietic and lymphoid tissues published by the World Health organization (WHO) in 2016 including (1) myeloid neoplasms with germ line predisposition without a pre-existing disorder or organ dysfunction, (2) myeloid neoplasms with germ line predisposition and pre-existing platelet disorder and (3) myeloid neoplasms with germ line predisposition and other organ

**26**

Fanconi anemia (FA) is a hereditary disorder with defects in DNA repair and is usually inherited as an autosomal recessive trait but it can be X-linked (FA

*FA, Fanconi anemia; DC, dyskeratosis congenita; SDS, Shwachman-Diamond syndrome; DBA, Diamond Blackfan anemia; CAMT, congenital amegakaryocytic thrombocytopenia; SCN, severecongenital neutropenia; AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive.*

#### **Table 1.**

*Common types of inherited bone marrow failure syndromes.*

*Data extracted from the Rockefeller University » Fanconi Anemia Mutation. Database at www.rockefeller.edu/ fanconi, Ref. [10].*

#### **Table 2.**

*Fanconi anemia genes and locations on chromosomes.*

complementation group B). Cells from patients with FA are more sensitive to chemotherapy than those from patients without FA, which can cause severe consequences from the normal dose of chemotherapies. So far, 22 genes responsible for FA have been identified [10]. In the general population, the complementation A occurs in about 60–70%, while complementation-C occurs in about 15% and the complementation-G occurs in about 10% of the total 22 FA responsible genes mutated with a vary of their subgroups in some geographical regions (**Table 2** and **Figure 1**).

Patients with FA are characterized with congenital abnormalities but progressive bone marrow failure is the most common characteristic, so it is named as IBMFS. FA also increases susceptibility to malignancies and individuals with FA also can suffer one or more types of cancers.

FA also has with variable congenital malformations and a predisposition to develop hematological or solid tumors, commonly in MDS, AML, and solid tumors, commonly carcinoma of the oropharynx and skin. Studies found the association of FA with a pattern of recurrent chromosomal abnormalities including monosomy chromosome 7, deletion of the long arm of chromosome 7, gain of the long arms of chromosome 3 and 1 and the RUNX1 gene mutations in about 20% of the combined MDS cases. Chromosome abnormalities with 7 and 3 had a poor prognostic indication value [11].

**29**

links [12].

**Figure 1.**

and sporadic cancers.

tion of FANCD2 and FANCI by monoubiquitination.

*Inherited Bone Marrow Failure and Chromosome Instability Syndromes and their Cancer…*

The FA pathways are defined from the encoded proteins work in concert in a distinct genomic maintenance. The FA pathways in normal cells are not constitutionally active but they are turned on during the S phase of the cell cycle in the presence of DNA damage to coordinate distinct repair functions in nucleotide excision, translesion synthesis and homologous recombination to remove the cross

*22 FA-genes identified on chromosome locations constructed from the data extracted from the Rockefeller*

*University Fanconi Anemia Mutation Database at: www.rockefeller.edu/fanconi. Ref. [10].*

The 22 FA gene products make up the FA pathways in the maintenance of genomic stability and the FA pathways can be activated by DNA damage and replication. The number of FA proteins reflects the complicated nature of the FA pathways. Mutation in any of the 22 FA genes causes defects in the response to DNA damage and repair results in disease of FA by the loss of DNA interstrand cross-links repair [13]. The FA pathways are the key event with the complex pathological mechanisms in DNA repair and cancer suppression in both inherited

The proteins involved in FA consist of several classes of enzymes and structural proteins, including ubiquitin ligase, monoubiquitinated proteins and helicase [14]. FA nuclear core protein complex consists of eight proteins, encoded by FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL and FANCM, with ubiquitin ligase activity. This protein complex is required for the critical monoubiquitination of FANCD2 and FANCI in response to DNA damage during replication. The biological functions of this protein complex are to maintain DNA stability and repair DNA damage protein-protein interactions are required for core complex protein stability form the stable core protein complex in function that is required for the modifica-

E3 ubiquitin-protein ligase FANCL belongs to the multi-subunit FA complex and is a ligase protein that mediates monoubiquitination of FANCD2, a key step in the repair of ICLs in the FA pathways [15]. FANCL is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair [16]. The monoubiquitination process of FANCD2 and FANCI recruits DNA repair machinery in order to maintain genomic integrity during cellular proliferation within certain tissues. Mutation in any member

*DOI: http://dx.doi.org/10.5772/intechopen.81546*

*Inherited Bone Marrow Failure and Chromosome Instability Syndromes and their Cancer… DOI: http://dx.doi.org/10.5772/intechopen.81546*

#### **Figure 1.**

*Contemporary Pediatric Hematology and Oncology*

**Complementation groups Gene's symbols Locations on chromosomes**

FA-A FANCA 16q24.3 FA-B FANCB Xp22.31 FA-C FANCC 9p22.3 FA-D1 FANCD1 13q12.3 FA-D2 FANCD2 3p25.3 FA-E FANCE 6p21.3 FA-F FANCF 11p15 FA-G FANCG 9p13 FA-I FANCI 15q26.1 FA-J FANCJ 17q22 FA-L FANCL 2p16.1 FA-M FANCM 14q21.3 FA-N FANCN 16p12 FA-O FANCO 17q25.1 FA-P FANCP 16p13.3 FA-Q FANCQ 16p13.12 FA-R FANCR 15q15 FA-S FANCS 17q21 FA-T FANCT 1q32.1 FA-U FANCU 7q36 FA-V FANCV 1p36 FA-W FANCW 16q22.3

complementation group B). Cells from patients with FA are more sensitive to chemotherapy than those from patients without FA, which can cause severe consequences from the normal dose of chemotherapies. So far, 22 genes responsible for FA have been identified [10]. In the general population, the complementation A occurs in about 60–70%, while complementation-C occurs in about 15% and the complementation-G occurs in about 10% of the total 22 FA responsible genes mutated with a vary of their subgroups in some geographical regions (**Table 2** and **Figure 1**).

*Data extracted from the Rockefeller University » Fanconi Anemia Mutation. Database at www.rockefeller.edu/*

Patients with FA are characterized with congenital abnormalities but progressive bone marrow failure is the most common characteristic, so it is named as IBMFS. FA also increases susceptibility to malignancies and individuals with FA also can suffer

FA also has with variable congenital malformations and a predisposition to develop hematological or solid tumors, commonly in MDS, AML, and solid tumors, commonly carcinoma of the oropharynx and skin. Studies found the association of FA with a pattern of recurrent chromosomal abnormalities including monosomy chromosome 7, deletion of the long arm of chromosome 7, gain of the long arms of chromosome 3 and 1 and the RUNX1 gene mutations in about 20% of the combined MDS cases. Chromosome abnormalities with 7 and 3 had a poor prognostic indication value [11].

**28**

one or more types of cancers.

*Fanconi anemia genes and locations on chromosomes.*

*fanconi, Ref. [10].*

**Table 2.**

*22 FA-genes identified on chromosome locations constructed from the data extracted from the Rockefeller University Fanconi Anemia Mutation Database at: www.rockefeller.edu/fanconi. Ref. [10].*

The FA pathways are defined from the encoded proteins work in concert in a distinct genomic maintenance. The FA pathways in normal cells are not constitutionally active but they are turned on during the S phase of the cell cycle in the presence of DNA damage to coordinate distinct repair functions in nucleotide excision, translesion synthesis and homologous recombination to remove the cross links [12].

The 22 FA gene products make up the FA pathways in the maintenance of genomic stability and the FA pathways can be activated by DNA damage and replication. The number of FA proteins reflects the complicated nature of the FA pathways. Mutation in any of the 22 FA genes causes defects in the response to DNA damage and repair results in disease of FA by the loss of DNA interstrand cross-links repair [13]. The FA pathways are the key event with the complex pathological mechanisms in DNA repair and cancer suppression in both inherited and sporadic cancers.

The proteins involved in FA consist of several classes of enzymes and structural proteins, including ubiquitin ligase, monoubiquitinated proteins and helicase [14]. FA nuclear core protein complex consists of eight proteins, encoded by FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL and FANCM, with ubiquitin ligase activity. This protein complex is required for the critical monoubiquitination of FANCD2 and FANCI in response to DNA damage during replication. The biological functions of this protein complex are to maintain DNA stability and repair DNA damage protein-protein interactions are required for core complex protein stability form the stable core protein complex in function that is required for the modification of FANCD2 and FANCI by monoubiquitination.

E3 ubiquitin-protein ligase FANCL belongs to the multi-subunit FA complex and is a ligase protein that mediates monoubiquitination of FANCD2, a key step in the repair of ICLs in the FA pathways [15]. FANCL is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair [16]. The monoubiquitination process of FANCD2 and FANCI recruits DNA repair machinery in order to maintain genomic integrity during cellular proliferation within certain tissues. Mutation in any member

of a core protein complex results in the loss of the monoubiquitination of the FANCI/FANCD2 complex step [17]. FANCD2 and FANCI proteins are substrates for ubiquitination with the two being similar in size and domain structure. This monoubiquitination is the crucial event of the FA pathways, and the monoubiquitination isoform of FANCD2 associates with the repair protein BRCA1 in DNA damage-induced nuclear foci. This foci formation is induced by both cross-linking agents and DNA-damaging agents and this process is regulated by the nuclear core protein complex [18].

The genetic association between cancers with FA and without FA gene mutation clinically has been intensively investigated and a close connection has been discovered between FA and tumorigenesis observed from both clinical and cellular phenotypes. Inherited homozygous (bi-allelic) mutations from germ line can cause FA phenotype and increase susceptibility to both hematologic and nonhematologic malignancies [19]. The first case of FA was recognized as a cause of Juvenile leukemia in 1967 [20]. Cancers with FA gene mutations are difficult to be treated (except surgically) because cells from patients with FA are more sensitive to chemotherapy and radiation comparing with non-FA cancers [21]. The relative risk of non-hematologic malignancies in patients with FA is increased commonly for squamous cell carcinomas (700 times greater than in normal population) including the head and neck, vulva, esophagus, gastric osteogenic sarcoma, cervix and skin. Many other types of cancers including breast cancer, lung cancer, colon cancer and brain tumor were found from patients with FA as well, with the median onset age of cancers being 16 years old in FA patients compared with 68 years in the non-FA population [22]. In addition, FA patients could develop different types of cancers.

The risk of developing to acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) has been reported to increase by 785-fold [23, 24]. It is estimated that acute myeloid leukemia from the germ line mutation associated cause is about 10–15% and it could be higher. Inherited germ line mutations are present in an increasing proportion of children, predisposing them to leukemia. Several genetic syndromes have been found to associate with leukemia/cancers and the best examples are IBMFS and CIS. The risk of leukemia/cancers and the outcome of these syndromes particularly in these with substantial proportion of patients with therapy related leukemia/cancer harbor germ line mutations in DNA damage and response genes such as BRCA1/2 and TP53.

To deal with germ line mutated leukemia, not only requires an increase in awareness of germ line mutations but also taking family history from patients and offering genetic counseling for the relevant to malignant diagnosis, it also requires an understanding of the developments of the genetic landscapes because the treatment strategy for IBMFS and CIS associated malignancies is different from the malignancies in the sporadic manner. The differential diagnosis on malignancies such as MDS, acute leukemia and solid tumors is imperative.

Studies showed that there was no increase of cancer risk from FA carriers in overall but there was evidence that these carriers from FANCC type mutation increase breast cancer risk, so it was suggested that carries of relatives of FANCC should carefully follow the recommendations for breast cancer screening [25].

However, an early and accurate diagnosis for FA is often difficult because FA is a genetically and phenotypically heterogeneous disease lacking specific and typical clinical features. Diagnosis in more or less cases can be delayed until bone marrow failure or cancer/leukemia occurs. As a result, Delayed or misdiagnosis or even wrong treatment received for patients with FA are not uncommon events clinically in some regions or countries due to the lack of recognition of FA from the clinicians and the limitation in testing resource in laboratory.

**31**

*Inherited Bone Marrow Failure and Chromosome Instability Syndromes and their Cancer…*

Dyskeratosis congenita (DC or DKC) is an inherited disease in autosomal dominant, autosomal recessive and X-linked patterns which is defined as one of the IBMFS characterized by the presence of bone marrow failure and the mucocutaneous triad of abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia [26]. Patients with DC increases the risk of MDS, AML and other types of cancers (carcinomas of the upper gastro-intestinal tract). Aplastic anemia, MDS and AML from patient with DC could be the early or first signs to be seen clinically. DC is the most typical representative type in IBMFS in telomere abnormality causing genomic instability due to the accelerated telomere shortening to result in cell loss or dysfunction and nine genes responsible for DC (DKC1, TERT, TERC, TINF2, RTEL1, NOP10, NHP2, WRAP53 and CTC1) the functioning and maintenance of

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by early onset exocrine pancreatic insufficiency, bone marrow failure and other genetic abnormalities. About 20% of SDS patients will develop MDS and 25% of patients with SDS will develop leukemia [28]. Deletion 5q, monosomy/ deletion of chromosomal 7q and 20q are the most frequent abnormalities in patients with SDS presenting with MDS but such types of chromosomal abnormalities do not contribute to leukemia transformation. Molecular studies showed about 90% of SDS patients have SBDS gene mutation and its product has an important role in the

Diamond-Blackfan anemia (DBA) is a rare, dominantly inherited syndrome characterized by bone marrow failure, birth defects, and a significant predisposition to cancer. The main clinical characteristics of DBA are the early infant anemia selectively in erythroid lineage (pure red cell aplasia) with some somatic abnormalities such as craniofacial thumb, cardiac and urogenital malformations [30] commonly develop to an increased predisposition to MDS, AML and other types of tumors has been reported [31]. DBA gene (RPS19) was identified in 1999 [32]. Subsequent studies found the heterozygous mutations in other encoding genes for ribosomal proteins of the small (RPS24, RPS17, RPS7, RPS10, RPS26) and large (RPL5, RPL11, RPL35) ribosomal subunits have also found to associated with DBA and RPS5 gene was found tend to have multiple physical abnormalities [33]. RPS19 mutations causing DBA showed ethnic difference in phenotype expression [34]. Recent studies using aCGH identified deletion of RPL15 as a novel cause of DBA [35].

Severe congenital neutropenia (SCN) is an autosomal recessive disorder characterized by early onset neutropenia and presented with recurrent life infections but early with physical abnormalities. SCN can develop to MDS and AML with the secondary mutations including the granulocyte colony stimulating factor receptor [36]. The neutrophil elastase gene (ELA2), defects in mitochondria gene (HAX1), deficiency in adenylate kinase 2 gene (AK2) and a other genes mutated (GFI1, WASP the transcriptional repressor and the cytoskeletal regulator, respectively) associated with apoptosis was found to responsible for SCN in at least 50% patients

*DOI: http://dx.doi.org/10.5772/intechopen.81546*

telomeres have been identified so far [27].

maturation of the 60S ribosomal subunit [29].

**2.4 Diamond-Blackfan anemia**

**2.5 Severe congenital neutropenia**

**2.3 Shwachman-Diamond syndrome**

**2.2 Dyskeratosis congenita**

*Inherited Bone Marrow Failure and Chromosome Instability Syndromes and their Cancer… DOI: http://dx.doi.org/10.5772/intechopen.81546*

#### **2.2 Dyskeratosis congenita**

*Contemporary Pediatric Hematology and Oncology*

protein complex [18].

different types of cancers.

response genes such as BRCA1/2 and TP53.

such as MDS, acute leukemia and solid tumors is imperative.

and the limitation in testing resource in laboratory.

of a core protein complex results in the loss of the monoubiquitination of the FANCI/FANCD2 complex step [17]. FANCD2 and FANCI proteins are substrates for ubiquitination with the two being similar in size and domain structure. This monoubiquitination is the crucial event of the FA pathways, and the monoubiquitination isoform of FANCD2 associates with the repair protein BRCA1 in DNA damage-induced nuclear foci. This foci formation is induced by both cross-linking agents and DNA-damaging agents and this process is regulated by the nuclear core

The genetic association between cancers with FA and without FA gene mutation clinically has been intensively investigated and a close connection has been discovered between FA and tumorigenesis observed from both clinical and cellular phenotypes. Inherited homozygous (bi-allelic) mutations from germ line can cause FA phenotype and increase susceptibility to both hematologic and nonhematologic malignancies [19]. The first case of FA was recognized as a cause of Juvenile leukemia in 1967 [20]. Cancers with FA gene mutations are difficult to be treated (except surgically) because cells from patients with FA are more sensitive to chemotherapy and radiation comparing with non-FA cancers [21]. The relative risk of non-hematologic malignancies in patients with FA is increased commonly for squamous cell carcinomas (700 times greater than in normal population) including the head and neck, vulva, esophagus, gastric osteogenic sarcoma, cervix and skin. Many other types of cancers including breast cancer, lung cancer, colon cancer and brain tumor were found from patients with FA as well, with the median onset age of cancers being 16 years old in FA patients compared with 68 years in the non-FA population [22]. In addition, FA patients could develop

The risk of developing to acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) has been reported to increase by 785-fold [23, 24]. It is estimated that acute myeloid leukemia from the germ line mutation associated cause is about 10–15% and it could be higher. Inherited germ line mutations are present in an increasing proportion of children, predisposing them to leukemia. Several genetic syndromes have been found to associate with leukemia/cancers and the best examples are IBMFS and CIS. The risk of leukemia/cancers and the outcome of these syndromes particularly in these with substantial proportion of patients with therapy related leukemia/cancer harbor germ line mutations in DNA damage and

To deal with germ line mutated leukemia, not only requires an increase in awareness of germ line mutations but also taking family history from patients and offering genetic counseling for the relevant to malignant diagnosis, it also requires an understanding of the developments of the genetic landscapes because the treatment strategy for IBMFS and CIS associated malignancies is different from the malignancies in the sporadic manner. The differential diagnosis on malignancies

Studies showed that there was no increase of cancer risk from FA carriers in overall but there was evidence that these carriers from FANCC type mutation increase breast cancer risk, so it was suggested that carries of relatives of FANCC should carefully follow the recommendations for breast cancer screening [25]. However, an early and accurate diagnosis for FA is often difficult because FA is a genetically and phenotypically heterogeneous disease lacking specific and typical clinical features. Diagnosis in more or less cases can be delayed until bone marrow failure or cancer/leukemia occurs. As a result, Delayed or misdiagnosis or even wrong treatment received for patients with FA are not uncommon events clinically in some regions or countries due to the lack of recognition of FA from the clinicians

**30**

Dyskeratosis congenita (DC or DKC) is an inherited disease in autosomal dominant, autosomal recessive and X-linked patterns which is defined as one of the IBMFS characterized by the presence of bone marrow failure and the mucocutaneous triad of abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia [26]. Patients with DC increases the risk of MDS, AML and other types of cancers (carcinomas of the upper gastro-intestinal tract). Aplastic anemia, MDS and AML from patient with DC could be the early or first signs to be seen clinically. DC is the most typical representative type in IBMFS in telomere abnormality causing genomic instability due to the accelerated telomere shortening to result in cell loss or dysfunction and nine genes responsible for DC (DKC1, TERT, TERC, TINF2, RTEL1, NOP10, NHP2, WRAP53 and CTC1) the functioning and maintenance of telomeres have been identified so far [27].

#### **2.3 Shwachman-Diamond syndrome**

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by early onset exocrine pancreatic insufficiency, bone marrow failure and other genetic abnormalities. About 20% of SDS patients will develop MDS and 25% of patients with SDS will develop leukemia [28]. Deletion 5q, monosomy/ deletion of chromosomal 7q and 20q are the most frequent abnormalities in patients with SDS presenting with MDS but such types of chromosomal abnormalities do not contribute to leukemia transformation. Molecular studies showed about 90% of SDS patients have SBDS gene mutation and its product has an important role in the maturation of the 60S ribosomal subunit [29].

#### **2.4 Diamond-Blackfan anemia**

Diamond-Blackfan anemia (DBA) is a rare, dominantly inherited syndrome characterized by bone marrow failure, birth defects, and a significant predisposition to cancer. The main clinical characteristics of DBA are the early infant anemia selectively in erythroid lineage (pure red cell aplasia) with some somatic abnormalities such as craniofacial thumb, cardiac and urogenital malformations [30] commonly develop to an increased predisposition to MDS, AML and other types of tumors has been reported [31]. DBA gene (RPS19) was identified in 1999 [32].

Subsequent studies found the heterozygous mutations in other encoding genes for ribosomal proteins of the small (RPS24, RPS17, RPS7, RPS10, RPS26) and large (RPL5, RPL11, RPL35) ribosomal subunits have also found to associated with DBA and RPS5 gene was found tend to have multiple physical abnormalities [33]. RPS19 mutations causing DBA showed ethnic difference in phenotype expression [34]. Recent studies using aCGH identified deletion of RPL15 as a novel cause of DBA [35].

#### **2.5 Severe congenital neutropenia**

Severe congenital neutropenia (SCN) is an autosomal recessive disorder characterized by early onset neutropenia and presented with recurrent life infections but early with physical abnormalities. SCN can develop to MDS and AML with the secondary mutations including the granulocyte colony stimulating factor receptor [36]. The neutrophil elastase gene (ELA2), defects in mitochondria gene (HAX1), deficiency in adenylate kinase 2 gene (AK2) and a other genes mutated (GFI1, WASP the transcriptional repressor and the cytoskeletal regulator, respectively) associated with apoptosis was found to responsible for SCN in at least 50% patients [37, 38]. Such genetic defects in multiple pathways causing congenital neutropenia are in the controlling of granulocytic progenitor differentiation.

#### **2.6 Congenital amegakaryocytic thrombocytopenia**

Congenital amegakaryocytic thrombocytopenia (CAMT) is characterized as hemorrhages or bruises associated with thrombocytopenia in infancy but rarely presents with physical defects. MDS and AML but not solid tumors associated with CAMT have been reported [39]. Molecular studies demonstrated the gene mutated called MPL (encoding of the receptor for thrombopoietin) is responsible for CAMT and showed the correlation between genotype and phenotype [40].

#### **2.7 Thrombocytopenia absent radii**

Studies found that thrombocytopenia absent radii (TAR) can be either in autosomal recessive or de novo pattern, typically seen in infants presenting with thrombocytopenia (low platelet count) and allergy to cow milk, physical characteristic of bilateral absent radii and other types of birth defects [41]. Similarly, acute leukemia and solid tumors have been reported from patients with TAR [42].

The pathological mechanism of thrombocytopenia was studied and the serum level of thrombopoietin (the megakaryocyte growth factor) was increased, suggesting the abnormal differentiation mechanism to megakaryocyte and platelet production [43].

The first molecular finding of interstitial microdeletion at chromosome 1q21.1 containing 10 genes including the TAR responsible gene-RBM8A by using comparative genomic hybridization (CGH) microarray technique was in 2007 [44]. Recent finding proved that RBM8A encodes the conserved Y14 subunit of the exon-junction complex that is essential for RNA processing and expressed in all hematopoietic lineages suggesting the cause of TAR [45].

#### **3. The common types of CIS**

Studies demonstrated that many types of rare genetic diseases associate chromosome instability typically seen in chromosome instability syndromes with shared clinical features each other. CIS is characterized by an increased frequency of spontaneous or induced chromosomal breaks/aberrations and increased risk of cancer due to the defects of DNA repair as Taylor has defined and described about their clinical features on the most common types of CIS in 2001 [46]. The common cause of chromosomal instability syndromes is the defects of genomic maintenance and DNA repair and they are overlapping and share some clinical features.

The chromosomal instability refers to the predisposition of the chromosomes to undergo rearrangements at the chromosomal level. For example, FA increased spontaneous and inducible chromosome breaks, Ataxia telangiectasia increase chromosome breaks presence of clones with translocations between chromosome 7,14 and X, BLOOM syndrome increased spontaneous and inducible SCE. They are all have increased spontaneous chromatid breaks of symmetrical quadriradials as their main cytogenetic features.

The common types of CIS are FA, Nijmegen breakage syndrome, Ataxia telangiectasia, Ataxia telangiectasia-like disorder and Bloom syndrome. The phenotype and genotype and their association with cancer are summarized in **Table 3**. Interestingly, FA fall into two classes of genetic syndromes: class one is IBMFS which

**33**

**3.1. Fanconi anemia**

*Inherited Bone Marrow Failure and Chromosome Instability Syndromes and their Cancer…*

Various FANC-A,

**Mutant genes**

B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T, U, V and W

8q21.3 Nbs1 BRCT-

11q23 ATM Protein

11q21 Mre11 Exonuclease/

**Protein functions**

containing protein

15q26.1 NLM DNA helicase Yes [57, 78]

kinase

endonuclease

**Cancer risk**

Various Yes [10, 79]

**References**

Yes [52, 79]

Yes [67, 73]

[74, 77]

Proposed but no report seen

**chromosomes**

has been discussed in the pathogenetic mechanism in the IBMFS part and class two

FA proteins maintain the genomic stability and repair the DNA damaged by factors. But under the condition of FA proteins defects, the damaged DNAs fail to be repaired as normal, resulting in FA clinical phenotypes. Because Fanconi anemia (FA) Cells from FA patients exhibit a hypersensitivity to DNA interstrand crosslinking agents a specific method named "Gold standard" and called "chromosomal fragility testing" using clastogenic agents, mitomycin C (MMC) and diepoxybutane (DEB) was found by Cervenka et al. in 1981 [47] and Auerbach in 1993 [48], respectively The principle of this method is to challenge the hyposensitive FA cells in the cell culture (most commonly T-lymphocytes from peripheral blood) exposed to DEB and MMC and then to analyze the chromosomal aberration, breaks, rearrangements and radials exchanges. A total 50 cells in metaphase are scored and analyzed for chromosomal breakages compared to controls in the same conditions including age and sex. It is positive if the total chromosome breakage is greater

is named as CIS with overlaps in the phenotypes with IBMFS (**Figure 2**).

Fanconi anemia

Nijmegen Breakage syndrome

Bloom's syndrome

Ataxia telangiectasia

Ataxia telangiectasialike disorder

**Table 3.**

*Inherited Bone Marrow Failure and Chromosome Instability Syndromes and their Cancer… DOI: http://dx.doi.org/10.5772/intechopen.81546*

#### **Table 3.**

*Contemporary Pediatric Hematology and Oncology*

**2.7 Thrombocytopenia absent radii**

production [43].

**3. The common types of CIS**

their main cytogenetic features.

[37, 38]. Such genetic defects in multiple pathways causing congenital neutropenia

Congenital amegakaryocytic thrombocytopenia (CAMT) is characterized as hemorrhages or bruises associated with thrombocytopenia in infancy but rarely presents with physical defects. MDS and AML but not solid tumors associated with CAMT have been reported [39]. Molecular studies demonstrated the gene mutated called MPL (encoding of the receptor for thrombopoietin) is responsible for CAMT

Studies found that thrombocytopenia absent radii (TAR) can be either in autosomal recessive or de novo pattern, typically seen in infants presenting with thrombocytopenia (low platelet count) and allergy to cow milk, physical characteristic of bilateral absent radii and other types of birth defects [41]. Similarly, acute leukemia

The pathological mechanism of thrombocytopenia was studied and the serum level of thrombopoietin (the megakaryocyte growth factor) was increased, suggesting the abnormal differentiation mechanism to megakaryocyte and platelet

The first molecular finding of interstitial microdeletion at chromosome 1q21.1 containing 10 genes including the TAR responsible gene-RBM8A by using comparative genomic hybridization (CGH) microarray technique was in 2007 [44]. Recent finding proved that RBM8A encodes the conserved Y14 subunit of the exon-junction complex that is essential for RNA processing and expressed in all

Studies demonstrated that many types of rare genetic diseases associate chromosome instability typically seen in chromosome instability syndromes with shared clinical features each other. CIS is characterized by an increased frequency of spontaneous or induced chromosomal breaks/aberrations and increased risk of cancer due to the defects of DNA repair as Taylor has defined and described about their clinical features on the most common types of CIS in 2001 [46]. The common cause of chromosomal instability syndromes is the defects of genomic maintenance

and DNA repair and they are overlapping and share some clinical features.

The common types of CIS are FA, Nijmegen breakage syndrome, Ataxia telangiectasia, Ataxia telangiectasia-like disorder and Bloom syndrome. The phenotype and genotype and their association with cancer are summarized in **Table 3**. Interestingly, FA fall into two classes of genetic syndromes: class one is IBMFS which

The chromosomal instability refers to the predisposition of the chromosomes to undergo rearrangements at the chromosomal level. For example, FA increased spontaneous and inducible chromosome breaks, Ataxia telangiectasia increase chromosome breaks presence of clones with translocations between chromosome 7,14 and X, BLOOM syndrome increased spontaneous and inducible SCE. They are all have increased spontaneous chromatid breaks of symmetrical quadriradials as

are in the controlling of granulocytic progenitor differentiation.

and showed the correlation between genotype and phenotype [40].

and solid tumors have been reported from patients with TAR [42].

hematopoietic lineages suggesting the cause of TAR [45].

**2.6 Congenital amegakaryocytic thrombocytopenia**

**32**

*Common types of chromosome instability syndromes.*

has been discussed in the pathogenetic mechanism in the IBMFS part and class two is named as CIS with overlaps in the phenotypes with IBMFS (**Figure 2**).

#### **3.1. Fanconi anemia**

FA proteins maintain the genomic stability and repair the DNA damaged by factors. But under the condition of FA proteins defects, the damaged DNAs fail to be repaired as normal, resulting in FA clinical phenotypes. Because Fanconi anemia (FA) Cells from FA patients exhibit a hypersensitivity to DNA interstrand crosslinking agents a specific method named "Gold standard" and called "chromosomal fragility testing" using clastogenic agents, mitomycin C (MMC) and diepoxybutane (DEB) was found by Cervenka et al. in 1981 [47] and Auerbach in 1993 [48], respectively The principle of this method is to challenge the hyposensitive FA cells in the cell culture (most commonly T-lymphocytes from peripheral blood) exposed to DEB and MMC and then to analyze the chromosomal aberration, breaks, rearrangements and radials exchanges. A total 50 cells in metaphase are scored and analyzed for chromosomal breakages compared to controls in the same conditions including age and sex. It is positive if the total chromosome breakage is greater

**Figure 2.** *Major types of CIS and IBMFS. FA overlaps with these two syndromes. Refs. [78, 79].*

than 10-fold comparing to control. A typical chromosome breakage of peripheral lymphocytes induced by MMC from patient with FA is shown in **Figure 3**.

In the last two decades, the method of chromosome fragility testing has been the most widely used as the first line laboratory screen for patients with congenital malformations even without anemia with the features of simple, reliable, reproducible and sensitive comparing with other testing methods in FA diagnosis although it is laborious and requires specialized personnel.

Chromosome fragility test method can differentiate between FA and non-FA cell usually but there are some limitations of this method: (1) it cannot detect the carriers, (2) it is often inconclusive in somatic mosaic cases of FA and (3) false positive results from this test can be seen under the condition that tested individual referred for excluding of FA is under treatment with radiotherapy or chemotherapy

**35**

*Inherited Bone Marrow Failure and Chromosome Instability Syndromes and their Cancer…*

primary complementation group result and molecular techniques.

Saharan African Black FANCG 637-643delTAACCGCC [49].

by sequencing the corresponding gene.

and a negative chromosomal breakage test [51].

dysplastic syndrome and acute myeloid leukemia.

in certain period of time. In the earlier times, the spontaneous chromosomal breakage as a marker for FA diagnostic testing was used but it was found the testing result was inconsistent. Spontaneous chromosomal breakage usually indicates a poor

The next generation sequencing method for FA testing is to confirm the results found by the chromosomal fragility testing and to identify the specific gene mutations of FA as the severity of the disease and the risk of developing aplastic anemia or malignancies related to the complementation groups. Mutation analysis is to identify the specific gene mutations from the proband after confirmation by the

The conventional Sanger sequencing technology-based mutation sequencing is complicated and time consuming, costly and may not detect all types of disease causing aberrations such as deep intronic mutations, large deletions and amplifications due to the presence of so many mutated genes involved in FA requiring many steps including DNA amplification, sequencing and detection of large deletions. Such testing usually needs to be done in laboratories with specific expertise.

Targeted mutation analysis is used as the clues to detect the common mutations detection. These clues include Ashkenazi Jewish FANCC IVS4 + 4 A>T or FANCD1/ BRCA2 6174delT; non-Ashkenazi Jewish Moroccan FANCA 2172-2173insG or FANCA 4275delT; Tunisian FANCA 890-893del; Indian FANCA 2574C>G (S858R); Israeli Arabs FANCA del ex 6-31, FANCA IVS 42-2A>C, and FANCG IVS4 + 3A>G; Japanese FANCC IVS4 + 4 A>T; Afrikaner FANCA del ex 12-31 and FANCA del ex 11-17; Brazil FANCA 3788-3790del; Spanish Gypsy FANCA 295C>T; and Sub-

The majority of patients with FA worldwide are the complementation A with several hundred mutations. Deletion/duplication analysis is also used to detect deletions of one or more exons or of an entire gene of any suspected case of FA. So the target sequence analysis is to be used for all the known genes associated with FA which usually is complicated by the number of genes to be analyzed, the large number of possible mutations in each gene, the presence of large insertions or deletions in some genes, and the large size of many of the FA-related genes. If the complementation group has been established the responsible mutation can be determined

The next generation sequencing (NGS) technology offers exciting promise, an effective and faster molecular diagnostics approach for FA gene studies which is able to perform the mutation analysis for FA genes without the requirement of complementation group testing step which the living cells are required. Ameziane

In the clinical practice, an early and accurate diagnosis of FA before the stage of bone marrow failure, cancer/leukemia is crucial for the adequate treatment such as stem cell transplantation, the prevention of serious medical complications and also for the properly management in the other caring areas including pediatric, hematology, immunology, endocrinology, reproductive/IVF, obstetrics and surgery and also an early diagnosis of FA will permits the exclusion of other diseases and precludes inappropriate management of hematologic diseases such as aplastic anemia, myelo-

et al. applied the next generation sequencing approach to identify BRCA2, FANCD2, FANCI and FANCL mutations in novel unclassified FA patients [50]. Practical experience proved that NGS is an effective molecular diagnostic approach for IBMFS and CIS, reducing the turnaround tine and the cost gas been becoming lower gradually, and is now a standard tool in the clinical application. Recently, Aslan D group has used the NGS technique and studied a FA case with subtle signs

*DOI: http://dx.doi.org/10.5772/intechopen.81546*

prognosis.

**Figure 3.** *Chromosomal/chromatid breaks as indicated by arrows induced by MMC from patient with FA.*

in certain period of time. In the earlier times, the spontaneous chromosomal breakage as a marker for FA diagnostic testing was used but it was found the testing result was inconsistent. Spontaneous chromosomal breakage usually indicates a poor prognosis.

The next generation sequencing method for FA testing is to confirm the results found by the chromosomal fragility testing and to identify the specific gene mutations of FA as the severity of the disease and the risk of developing aplastic anemia or malignancies related to the complementation groups. Mutation analysis is to identify the specific gene mutations from the proband after confirmation by the primary complementation group result and molecular techniques.

The conventional Sanger sequencing technology-based mutation sequencing is complicated and time consuming, costly and may not detect all types of disease causing aberrations such as deep intronic mutations, large deletions and amplifications due to the presence of so many mutated genes involved in FA requiring many steps including DNA amplification, sequencing and detection of large deletions. Such testing usually needs to be done in laboratories with specific expertise.

Targeted mutation analysis is used as the clues to detect the common mutations detection. These clues include Ashkenazi Jewish FANCC IVS4 + 4 A>T or FANCD1/ BRCA2 6174delT; non-Ashkenazi Jewish Moroccan FANCA 2172-2173insG or FANCA 4275delT; Tunisian FANCA 890-893del; Indian FANCA 2574C>G (S858R); Israeli Arabs FANCA del ex 6-31, FANCA IVS 42-2A>C, and FANCG IVS4 + 3A>G; Japanese FANCC IVS4 + 4 A>T; Afrikaner FANCA del ex 12-31 and FANCA del ex 11-17; Brazil FANCA 3788-3790del; Spanish Gypsy FANCA 295C>T; and Sub-Saharan African Black FANCG 637-643delTAACCGCC [49].

The majority of patients with FA worldwide are the complementation A with several hundred mutations. Deletion/duplication analysis is also used to detect deletions of one or more exons or of an entire gene of any suspected case of FA. So the target sequence analysis is to be used for all the known genes associated with FA which usually is complicated by the number of genes to be analyzed, the large number of possible mutations in each gene, the presence of large insertions or deletions in some genes, and the large size of many of the FA-related genes. If the complementation group has been established the responsible mutation can be determined by sequencing the corresponding gene.

The next generation sequencing (NGS) technology offers exciting promise, an effective and faster molecular diagnostics approach for FA gene studies which is able to perform the mutation analysis for FA genes without the requirement of complementation group testing step which the living cells are required. Ameziane et al. applied the next generation sequencing approach to identify BRCA2, FANCD2, FANCI and FANCL mutations in novel unclassified FA patients [50]. Practical experience proved that NGS is an effective molecular diagnostic approach for IBMFS and CIS, reducing the turnaround tine and the cost gas been becoming lower gradually, and is now a standard tool in the clinical application. Recently, Aslan D group has used the NGS technique and studied a FA case with subtle signs and a negative chromosomal breakage test [51].

In the clinical practice, an early and accurate diagnosis of FA before the stage of bone marrow failure, cancer/leukemia is crucial for the adequate treatment such as stem cell transplantation, the prevention of serious medical complications and also for the properly management in the other caring areas including pediatric, hematology, immunology, endocrinology, reproductive/IVF, obstetrics and surgery and also an early diagnosis of FA will permits the exclusion of other diseases and precludes inappropriate management of hematologic diseases such as aplastic anemia, myelodysplastic syndrome and acute myeloid leukemia.

*Contemporary Pediatric Hematology and Oncology*

than 10-fold comparing to control. A typical chromosome breakage of peripheral

In the last two decades, the method of chromosome fragility testing has been the most widely used as the first line laboratory screen for patients with congenital malformations even without anemia with the features of simple, reliable, reproducible and sensitive comparing with other testing methods in FA diagnosis although it

Chromosome fragility test method can differentiate between FA and non-FA cell usually but there are some limitations of this method: (1) it cannot detect the carriers, (2) it is often inconclusive in somatic mosaic cases of FA and (3) false positive results from this test can be seen under the condition that tested individual referred for excluding of FA is under treatment with radiotherapy or chemotherapy

lymphocytes induced by MMC from patient with FA is shown in **Figure 3**.

*Chromosomal/chromatid breaks as indicated by arrows induced by MMC from patient with FA.*

*Major types of CIS and IBMFS. FA overlaps with these two syndromes. Refs. [78, 79].*

is laborious and requires specialized personnel.

**34**

**Figure 3.**

**Figure 2.**

### **3.2 Nijmegen syndrome**

Nijmegen syndrome (NS) is named from the Dutch city Nijmegen where the condition was first described. It is also named Berlin breakage syndrome, Ataxia Telangiectasia variant 1. NS is an autosomal recessive inherited disease with a complex health problematic conditions typically characterized (NS) by short stature, microcephaly, distinctive facial feature, recurrent respiratory tract infections, mental development delay from infancy to childhood, dysfunctional immune deficiency in T cells and low level of immunoglobulin G and A and increased susceptibility to infections. Individuals with NS increased risk of cancer development (>50 times), commonly in Hodgkin lymphoma, brain tumor, rhabdomyosarcoma about 40% of the affected individuals and usual before age 15. Studies showed heterozygous mutation increase cancer occurrence as well [52].

It is estimated that the prevalence of Nijmegen syndrome is in approximately 100,000 newborns although the exact data is still unknown [53]. Most individuals with NS have West Slavic origins and the largest number of them live in Poland. In the clinical presentation and laboratory diagnostic testing, Nijmegen syndrome and Fanconi anemia show biological overlap. A positive result of chromosomal breakage induced with clastogens such as MMC and DEB can be seen both in Fanconi anemia and Nijmegen syndrome. Translocations or inversions between chromosomes 7 and 14 can be seen its feature in Nijmegen syndrome [54].

The genetic cause of NS is due to the mutation of NBN gene mutation with homozygous c.657\_661del5 on chromosome 8q21.3, resulting in nibrin protein dysfunction which is involved in several critical cellular functions, including the repair of damaged DNA to maintain the stability of the genomic function when breaks of DNA strands happen in the stage where the genetic material in chromosomes exchanges for cell division. As a result, affected individuals are sensitive to radiation and other agent exposures [55, 56]. The molecular tests to confirm the diagnosis of a suspected proband are the analysis of exon 6 to determine if the c.657\_661 del5 allele and the analysis of entire NBN gene by the sequencing method.

#### **3.3 Bloom syndrome**

Bloom syndrome (BSyn) is also named as Bloom-Torre-Machacek syndrome and Bloom-Torre-Machacek syndrome. BSyn is an autosomal recessive pattern characterized with short stature, learning disability, a skin rash, sensitive to sun exposure, serious medical complications such as mild immune-deficiency, chronic obstructive pulmonary disease, varying degree of infertility in both male and female, increased risk of diabetes. Increased risk of cancers to 5–8-folds in earlier life, commonly seen myelodysplasia, leukemia, lymphoma, adenocarcinoma and other types of cancers in epithelial tissues are the characteristics of BSyn as well [57]. Cytogenetics findings are the aberrant chromosomal rearrangements including quadriradial, chromatid gaps and breaks, increased frequency of SCE from the cultured lymphocytes [58].

Molecular studies demonstrated that mutation of BLM gene which is a 4528 bp cDNA sequence defines BLM containing a long open reading frame encoding a 1417-amino acid protein with 22 exons and is located on chromosome 15q26.1 resulted in RecQ helicase dysfunction in BLM protein is the cause of this disease. The BLM protein helps to maintain genome stability and integrity as the caretakers of the genome and also prevents the excess sister chromatid exchanges [59–62]. As a result, SCE is increased to 10-folds under the condition BLM gene mutated. In addition, chromosomal breakage is increased in individuals with Bloom syndrome [63–66].

**37**

**4. Conclusions**

*Inherited Bone Marrow Failure and Chromosome Instability Syndromes and their Cancer…*

Ataxia telangiectasia (AT) is an autosomal recessive inherited disorder first described in 1926 by two French physicians, Syllaba and Henner [67]. AT is also known as Boder-Sedgwick syndrome or Louis–Bar syndrome and its characteristics including a progressive loss of muscular coordination (ataxia), small cerebellum observed by MRI, increased alpha-fetal protein level and dilated blood vessels in the skin (telangiectasia) caused by a defect in ATM gene. AT affected 1 in 40,000 to 100,000 people worldwide [68] and also affects the nervous, immune and other body systems [69]. The ATM gene provides instructions for making the phosphatidylinositol 3-kinase protein to help control cell division in the normal development and DNA repair [70–72]. Studies demonstrated that increased cancer risk including T-cell leukemia, B-cell type of lymphoma usually, other types of cancers such as ovarian, breast, gastric cancers, melanoma and sarcoma have been reported [73]. Molecular studies revealed the mutations in the ATM gene with several allelic variants located on chromosome 11q23 are responsible for Ataxia-telangiectasia due to the defects in providing instructions for making the specific protein to help in controlling of cell division, DNA repair and in the normal biological development

and function of the body particularly in nervous and immune systems.

biological function of MERA11 protein is linked to Nbs1 in DNA repair.

tory in the slow technologies available at that time.

whole-exome, and transcriptome sequencing.

In the past decades, the diagnosis of IBMFS and CIS were limited by the few numbers of cases reported, uneven clinical features and the tests from the labora-

Thanks to the Human Genome Project, researchers have begun to understand the blueprint of the human genome by learning more about the structures and functions of human genes and proteins. With the application of new technologies for the studies, the concept and practice of genetic disease have been profoundly changing. The next generation sequencing technology has also been remarkably successful in the identification of causes of genetic diseases using whole-genome,

The studies on IBMFS and CIS have been offering a lot of opportunities by increasing our understanding of the correlations between phenotype and genotype and such studies have been enlightening the other areas particularly in personalized

Ataxia telangiectasia-like disorder (ATLD) is a rare autosomal recessive disorder

characterized by progressive cerebellar degeneration that shares many clinical presentations with Ataxia telangiectasia but without immune deficiency and telangiectasia, no cancer case report found. It was first designed in 1999 [74] and molecular studies showed that ATLD is caused by inactivating mutations of genes in either homozygous or compound heterozygous [75]. ATLD is usually diagnosed at young at the age starting to walk lacking of coordination and imbalance [76]. Studies showed that there are two mutated genes responsible for ATLD either in homozygous or compound heterozygous. The first is MER11A gene on chromosome 11q21 (ATLD-1) more than 10 different types of variants and the other one is PCNA gene on chromosome 20p12 [77]. Cells from patients demonstrated increased susceptibility to radiation due to the defect of DNA repair pathway. The ATM and MER11A genes are located on the long arm of chromosome 11closely and the

*DOI: http://dx.doi.org/10.5772/intechopen.81546*

**3.5 Ataxia telangiectasia-like disorder**

**3.4 Ataxia telangiectasia**

*Inherited Bone Marrow Failure and Chromosome Instability Syndromes and their Cancer… DOI: http://dx.doi.org/10.5772/intechopen.81546*

#### **3.4 Ataxia telangiectasia**

*Contemporary Pediatric Hematology and Oncology*

mutation increase cancer occurrence as well [52].

14 can be seen its feature in Nijmegen syndrome [54].

Nijmegen syndrome (NS) is named from the Dutch city Nijmegen where the condition was first described. It is also named Berlin breakage syndrome, Ataxia Telangiectasia variant 1. NS is an autosomal recessive inherited disease with a complex health problematic conditions typically characterized (NS) by short stature, microcephaly, distinctive facial feature, recurrent respiratory tract infections, mental development delay from infancy to childhood, dysfunctional immune deficiency in T cells and low level of immunoglobulin G and A and increased susceptibility to infections. Individuals with NS increased risk of cancer development (>50 times), commonly in Hodgkin lymphoma, brain tumor, rhabdomyosarcoma about 40% of the affected individuals and usual before age 15. Studies showed heterozygous

It is estimated that the prevalence of Nijmegen syndrome is in approximately 100,000 newborns although the exact data is still unknown [53]. Most individuals with NS have West Slavic origins and the largest number of them live in Poland. In the clinical presentation and laboratory diagnostic testing, Nijmegen syndrome and Fanconi anemia show biological overlap. A positive result of chromosomal breakage induced with clastogens such as MMC and DEB can be seen both in Fanconi anemia and Nijmegen syndrome. Translocations or inversions between chromosomes 7 and

The genetic cause of NS is due to the mutation of NBN gene mutation with homozygous c.657\_661del5 on chromosome 8q21.3, resulting in nibrin protein dysfunction which is involved in several critical cellular functions, including the repair of damaged DNA to maintain the stability of the genomic function when breaks of DNA strands happen in the stage where the genetic material in chromosomes exchanges for cell division. As a result, affected individuals are sensitive to radiation and other agent exposures [55, 56]. The molecular tests to confirm the diagnosis of a suspected proband are the analysis of exon 6 to determine if the c.657\_661 del5

Bloom syndrome (BSyn) is also named as Bloom-Torre-Machacek syndrome and Bloom-Torre-Machacek syndrome. BSyn is an autosomal recessive pattern characterized with short stature, learning disability, a skin rash, sensitive to sun exposure, serious medical complications such as mild immune-deficiency, chronic obstructive pulmonary disease, varying degree of infertility in both male and female, increased risk of diabetes. Increased risk of cancers to 5–8-folds in earlier life, commonly seen myelodysplasia, leukemia, lymphoma, adenocarcinoma and other types of cancers in epithelial tissues are the characteristics of BSyn as well [57]. Cytogenetics findings are the aberrant chromosomal rearrangements including quadriradial, chromatid gaps and breaks, increased frequency of SCE from the cultured lympho-

Molecular studies demonstrated that mutation of BLM gene which is a 4528 bp cDNA sequence defines BLM containing a long open reading frame encoding a 1417-amino acid protein with 22 exons and is located on chromosome 15q26.1 resulted in RecQ helicase dysfunction in BLM protein is the cause of this disease. The BLM protein helps to maintain genome stability and integrity as the caretakers of the genome and also prevents the excess sister chromatid exchanges [59–62]. As a result, SCE is increased to 10-folds under the condition BLM gene mutated. In addition, chromosomal breakage is increased in individuals with

allele and the analysis of entire NBN gene by the sequencing method.

**3.2 Nijmegen syndrome**

**3.3 Bloom syndrome**

**36**

cytes [58].

Bloom syndrome [63–66].

Ataxia telangiectasia (AT) is an autosomal recessive inherited disorder first described in 1926 by two French physicians, Syllaba and Henner [67]. AT is also known as Boder-Sedgwick syndrome or Louis–Bar syndrome and its characteristics including a progressive loss of muscular coordination (ataxia), small cerebellum observed by MRI, increased alpha-fetal protein level and dilated blood vessels in the skin (telangiectasia) caused by a defect in ATM gene. AT affected 1 in 40,000 to 100,000 people worldwide [68] and also affects the nervous, immune and other body systems [69]. The ATM gene provides instructions for making the phosphatidylinositol 3-kinase protein to help control cell division in the normal development and DNA repair [70–72]. Studies demonstrated that increased cancer risk including T-cell leukemia, B-cell type of lymphoma usually, other types of cancers such as ovarian, breast, gastric cancers, melanoma and sarcoma have been reported [73].

Molecular studies revealed the mutations in the ATM gene with several allelic variants located on chromosome 11q23 are responsible for Ataxia-telangiectasia due to the defects in providing instructions for making the specific protein to help in controlling of cell division, DNA repair and in the normal biological development and function of the body particularly in nervous and immune systems.

#### **3.5 Ataxia telangiectasia-like disorder**

Ataxia telangiectasia-like disorder (ATLD) is a rare autosomal recessive disorder characterized by progressive cerebellar degeneration that shares many clinical presentations with Ataxia telangiectasia but without immune deficiency and telangiectasia, no cancer case report found. It was first designed in 1999 [74] and molecular studies showed that ATLD is caused by inactivating mutations of genes in either homozygous or compound heterozygous [75]. ATLD is usually diagnosed at young at the age starting to walk lacking of coordination and imbalance [76].

Studies showed that there are two mutated genes responsible for ATLD either in homozygous or compound heterozygous. The first is MER11A gene on chromosome 11q21 (ATLD-1) more than 10 different types of variants and the other one is PCNA gene on chromosome 20p12 [77]. Cells from patients demonstrated increased susceptibility to radiation due to the defect of DNA repair pathway. The ATM and MER11A genes are located on the long arm of chromosome 11closely and the biological function of MERA11 protein is linked to Nbs1 in DNA repair.

### **4. Conclusions**

In the past decades, the diagnosis of IBMFS and CIS were limited by the few numbers of cases reported, uneven clinical features and the tests from the laboratory in the slow technologies available at that time.

Thanks to the Human Genome Project, researchers have begun to understand the blueprint of the human genome by learning more about the structures and functions of human genes and proteins. With the application of new technologies for the studies, the concept and practice of genetic disease have been profoundly changing. The next generation sequencing technology has also been remarkably successful in the identification of causes of genetic diseases using whole-genome, whole-exome, and transcriptome sequencing.

The studies on IBMFS and CIS have been offering a lot of opportunities by increasing our understanding of the correlations between phenotype and genotype and such studies have been enlightening the other areas particularly in personalized medicine. Such advances resulted in an unprecedented boom in medical research and an abundance of discoveries linking genetic variants to an assortment of diseases including various cancers. They also have been impacting the genetic field, integrating genomic medicine to primary healthcare practice, bridging the gap between the basic research and clinical application and revealing the pathological basis of genetic diseases which allows the development of accurate and specific tests for disease diagnosis and the eventual translation of research knowledge to clinical therapies.

There are a lot of challenges facing in such a field. Even up to now not all subtypes of IBMFs and CIS are well documented for the clinical and laboratory diagnostic criteria and guidelines due to the disease heterogeneous complexity of the disease, particularly in the developing counties. The clinical manifestations of such patients are highly variable so delay, misdiagnosis and mistreatment were not uncommon under the condition in which such syndromes were treated, that is, with the normal dosage for radiation/chemotherapy. Clinicians working in the field of IBMFS and CIS require a broad clinical knowledge on genetics, hematological and oncological aspects and the ability to refer such patients for testing as well as an experienced laboratory able to perform the particular testing and to translate the laboratory findings correctly into clinical practice. These are the prerequisites for diagnosis of the IBMFS and CIS as well. So cooperation of Multi-displines including genetics, hematology, endocrinendonology, immunology, microbiology, oncology and surgical in the clinic is required for a team in the diagnosis and treatment and also is required from cellular, protein and molecular levels in the laboratory testing, generally performed in a qualified and experienced laboratory. Diagnosis and differential diagnosis on IBMFS and CIS can be difficult sometimes due to the nature of disease and the lack of the specific techniques. Inherited cancer can be the early presentation of the disease as a reason.

Diagnosis on patients with IBMFS and CIS also is challenging, particularly in its early phase. Mismanagement from the misdiagnosis of IBMFS and CIS was not uncommon in some regions and countries because IBMFS and CIS is a genetically and phenotypically heterogeneous disease and also because IBMFS and CIS share many clinical features with several group diseases/syndromes. In research, the precise biological activities and the roles of the FA proteins remain still undetermined because most FA proteins in the core complex have no enzymatic motif which is an obstacle to understanding their molecular functions.

However, from a diagnostic perspective, we are still expecting the development of the ideal technologies for genetic disease testing with the features of specificity, sensitivity, accuracy, reliability, high throughput capacity, reproducibility, low cost and ease of operation because about 45% of patients with IBMFS and CIS need to be identified genetically. Furthermore, despite our vastly improved knowledge of human genetic variations, studying associations between genetic disease genotype and phenotype still remains a major challenge and there are many of mysteries unknown in the functional genetics causing diseases.

**39**

**Author details**

Zhan He Wu

provided the original work is properly cited.

Hospital at Westmead, NSW, Australia

\*Address all correspondence to<EMAIL_ADDRESS>
© 2018 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,

Sydney Genome Diagnostics, Western Sydney Genetics Program, The Children's

*Inherited Bone Marrow Failure and Chromosome Instability Syndromes and their Cancer…*

*DOI: http://dx.doi.org/10.5772/intechopen.81546*

*Inherited Bone Marrow Failure and Chromosome Instability Syndromes and their Cancer… DOI: http://dx.doi.org/10.5772/intechopen.81546*

## **Author details**

*Contemporary Pediatric Hematology and Oncology*

presentation of the disease as a reason.

obstacle to understanding their molecular functions.

unknown in the functional genetics causing diseases.

therapies.

medicine. Such advances resulted in an unprecedented boom in medical research and an abundance of discoveries linking genetic variants to an assortment of diseases including various cancers. They also have been impacting the genetic field, integrating genomic medicine to primary healthcare practice, bridging the gap between the basic research and clinical application and revealing the pathological basis of genetic diseases which allows the development of accurate and specific tests for disease diagnosis and the eventual translation of research knowledge to clinical

There are a lot of challenges facing in such a field. Even up to now not all subtypes of IBMFs and CIS are well documented for the clinical and laboratory diagnostic criteria and guidelines due to the disease heterogeneous complexity of the disease, particularly in the developing counties. The clinical manifestations of such patients are highly variable so delay, misdiagnosis and mistreatment were not uncommon under the condition in which such syndromes were treated, that is, with the normal dosage for radiation/chemotherapy. Clinicians working in the field of IBMFS and CIS require a broad clinical knowledge on genetics, hematological and oncological aspects and the ability to refer such patients for testing as well as an experienced laboratory able to perform the particular testing and to translate the laboratory findings correctly into clinical practice. These are the prerequisites for diagnosis of the IBMFS and CIS as well. So cooperation of Multi-displines including genetics, hematology, endocrinendonology, immunology, microbiology, oncology and surgical in the clinic is required for a team in the diagnosis and treatment and also is required from cellular, protein and molecular levels in the laboratory testing, generally performed in a qualified and experienced laboratory. Diagnosis and differential diagnosis on IBMFS and CIS can be difficult sometimes due to the nature of disease and the lack of the specific techniques. Inherited cancer can be the early

Diagnosis on patients with IBMFS and CIS also is challenging, particularly in its early phase. Mismanagement from the misdiagnosis of IBMFS and CIS was not uncommon in some regions and countries because IBMFS and CIS is a genetically and phenotypically heterogeneous disease and also because IBMFS and CIS share many clinical features with several group diseases/syndromes. In research, the precise biological activities and the roles of the FA proteins remain still undetermined because most FA proteins in the core complex have no enzymatic motif which is an

However, from a diagnostic perspective, we are still expecting the development of the ideal technologies for genetic disease testing with the features of specificity, sensitivity, accuracy, reliability, high throughput capacity, reproducibility, low cost and ease of operation because about 45% of patients with IBMFS and CIS need to be identified genetically. Furthermore, despite our vastly improved knowledge of human genetic variations, studying associations between genetic disease genotype and phenotype still remains a major challenge and there are many of mysteries

**38**

Zhan He Wu Sydney Genome Diagnostics, Western Sydney Genetics Program, The Children's Hospital at Westmead, NSW, Australia

\*Address all correspondence to<EMAIL_ADDRESS>
© 2018 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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Section 4

Malignant Tumors in

Children

45

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Section 4

## Malignant Tumors in Children

*Contemporary Pediatric Hematology and Oncology*

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[74] Taylor AM, Groom A, Byrd PJ. Ataxia-telangiectasia-like disorder (ATLD)-its clinical presentation and molecular basis. DNA Repair.

[75] Delia D, Piane M, Buscemi G, et al. MRE11 mutations and impaired ATM-dependent responses in an Italian family with ataxia-telangiectasia-like disorder. Human Molecular Genetics.

[76] Hernandez D, McConville CM, Stacey M, et al. A family showing no evidence of linkage between the ataxia telangiectasia gene and chromosome 11q22-23. Journal of Medical Genetics.

[77] Stewart GS, Maser RS, Stankovic T, et al. The DNA double-strand break repair gene hMRE11 is mutated

in individuals with an ataxiatelangiectasia-like disorder. Cell.

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2005;**58**:1009-1015

2005;**227**:105-114

2004;**3**(8-9):1219-1225

2004;**13**:2155-2163

1993;**30**:135-140

1999;**99**:577-587

Springer; 2006

ed. 2017. pp. 653-662

**44**

Chapter 4

Abstract

in Children

Maxim Yu. Rykov

children: hemoblastosis and solid tumors.

achieve remission in a significant number of patients.

of "oncological alertness" of pediatricians.

diagnostics, clinical symptoms

1. Introduction

47

Clinical Manifestations and

Diagnosis of Malignant Tumors

Pediatric oncology is a complex specialty, requiring the involvement of various specialists—pediatric oncologists, pathomorphologists, radiation diagnosticians, and surgeons. The patient's life depends, first of all, on the timeliness of the diagnosis, since the earlier the specialized treatment is started, the higher the probability of achieving remission. Of particular relevance is the problem of early detection of malignant neoplasms. The complexity of solving this problem is related to the atypical nature of the oncological diseases and their rarity, which leads to the lack of "oncological alertness" of primary care physicians—district pediatricians. It is from pediatricians that timely diagnosis of malignant neoplasms depends. This lecture is devoted to the clinical manifestations and diagnosis of malignant neoplasms in

Keywords: pediatric oncology, malignant tumors, solid tumors, hemoblastoses,

The problems of treating children with oncological diseases are relevant all over

the world. Successes associated with the introduction of intensive protocols of chemotherapy, bone marrow transplantation, organ-preserving treatment can

It is known that the earlier a specialized treatment is started, the higher the probability of a favorable outcome. Thus, treatment started in the early stages of the disease with nephroblastoma allows to achieve remission in 95% of patients, in osteosarcoma—in 70%, in Ewing sarcoma—in 65%, in rhabdomyosarcoma—in 59%. If the disease is found in common stages, this indicator is significantly lower. For example, for the abovementioned nosologies, it is 25, 6, 7, and 8%, respectively [1]. In this connection, the problem of early detection of malignant neoplasms is of particular urgency. The complexity of solving this problem is related to the atypical nature of the oncological diseases and their rarity, which, in turn, leads to the lack

A pediatrician, like a doctor of any other specialty, rarely has to deal with children affected by malignant tumors. For his medical practice, the average pediatrician meets about eight children with true tumors. It is with this that possible

### Chapter 4

## Clinical Manifestations and Diagnosis of Malignant Tumors in Children

Maxim Yu. Rykov

### Abstract

Pediatric oncology is a complex specialty, requiring the involvement of various specialists—pediatric oncologists, pathomorphologists, radiation diagnosticians, and surgeons. The patient's life depends, first of all, on the timeliness of the diagnosis, since the earlier the specialized treatment is started, the higher the probability of achieving remission. Of particular relevance is the problem of early detection of malignant neoplasms. The complexity of solving this problem is related to the atypical nature of the oncological diseases and their rarity, which leads to the lack of "oncological alertness" of primary care physicians—district pediatricians. It is from pediatricians that timely diagnosis of malignant neoplasms depends. This lecture is devoted to the clinical manifestations and diagnosis of malignant neoplasms in children: hemoblastosis and solid tumors.

Keywords: pediatric oncology, malignant tumors, solid tumors, hemoblastoses, diagnostics, clinical symptoms

#### 1.  Successes associated with the introduction of intensive protocols of chemotherapy, bone marrow transplantation, organ-preserving treatment can achieve remission in a significant number of patients.

It is known that the earlier a specialized treatment is started, the higher the probability of a favorable outcome. Thus, treatment started in the early stages of the disease with nephroblastoma allows to achieve remission in 95% of patients, in osteosarcoma—in 70%, in Ewing sarcoma—in 65%, in rhabdomyosarcoma—in 59%. If the disease is found in common stages, this indicator is significantly lower. For example, for the abovementioned nosologies, it is 25, 6, 7, and 8%, respectively [1].

In this connection, the problem of early detection of malignant neoplasms is of particular urgency. The complexity of solving this problem is related to the atypical nature of the oncological diseases and their rarity, which, in turn, leads to the lack of "oncological alertness" of pediatricians.

A pediatrician, like a doctor of any other specialty, rarely has to deal with children affected by malignant tumors. For his medical practice, the average pediatrician meets about eight children with true tumors. It is with this that possible

errors in diagnosis and, as a consequence, in treatment are connected. The patient's life depends, first of all, on the timely diagnosis, therefore, directly from the "oncological alertness" of the pediatrician.

Primary tumor symptom complex most often includes hypodynamia, lack of

These manifestations are caused by nonspecific reactions on the part of organs and systems or by ectopic production of a biologically active substance (hormones, proteins, growth factors, cytokines, antibodies), which causes a pathological increase in cell activity and forms certain manifestations, for example, Cushing's

In the pathogenesis of the development of the primary tumor symptom complex, the response of the immune system is important in response to the presence of a tumor, an immunologically foreign antigen. This is the basis for the development of clinical symptoms of dermatomyositis, rheumatoid arthritis, autoimmune

In some cases, the primary tumor symptom complex precedes the local symptoms of the tumor, whereas in others, it manifests simultaneously with them, sometimes will be added after the verification of the tumor process. The greatest difficulties arise in cases when the manifestations of the primary tumor symptom complex are treated as independent diseases or syndromes, which lead to the appointment of unjustified treatment and detection of malignant neoplasms at

Primary tumor symptom complex in the verification of malignant neoplasms is observed in 15% of patients, 50% of its manifestations develop during treatment, 35% in the late stages of the disease. Regression of the manifestations of the primary tumor symptom complex correlates with the tumor response to the therapy [2]. Leukemia is the most common tumor disease of childhood, which occurs mainly in the first 5–7 years of life. Among all leukemias in children, unlike adults, the vast

Acute leukemias (AL) are clonal diseases that arise from a single mutated hematopoietic cell, which refers either to very early ones or to the cells of predecessors committed to different hematopoiesis lines. Thus, AL is a malignant tumor that originates from blast cells. The diagnosis of AL is established in the event that the number of blast cells in the bone marrow exceeds 25% [3].

AL in children of morphological origin is divided into acute lymphoblastic (80%) and acute nonlymphoblastic (20%) leukemia, which differ from each other both biologically and clinically, but in all cases, the clinical course is

characterized by a high rate of increase in symptoms leading to rapid death of the

Clinical manifestations. In the clinical picture of AL, it is usually noted the presence of various symptomatic complexes, the most frequent among which are:

1. Intoxicative-inflammatory syndrome, which is manifested by lethargy, lethargy, loss of appetite, loss of body weight, unaccountable fever. This is a consequence, first of all, of reducing immunity due to a decrease in the number of leukocytes of the granulocyte germ (in the first place—neutrophils). These children have frequent recurrent inflammatory inflammatory diseases over

2. Anemia syndrome, the main manifestations of which are a decrease in the level of hemoglobin, erythrocytes, pallor of the skin and mucous membranes,

3. Hemorrhagic syndrome, in which there are polymorphic hemorrhages in the skin of the body and mucous membranes, bleeding (nasal, gastrointestinal,

appetite, weight loss, lethargy, weakness, fatigue, capriciousness, anemia,

Clinical Manifestations and Diagnosis of Malignant Tumors in Children

subfebrile condition, and dermatitis.

DOI: http://dx.doi.org/10.5772/intechopen.77362

syndrome, fever, and erythrocytosis.

later stages.

patient [3, 4].

49

short time intervals;

dyspnea, tachycardia due to hemic hypoxia;

hemolytic anemia, and other systemic manifestations.

majority (more than 95%) falls on acute forms.

### 2. Epidemiology of malignant tumors

In the structure of malignant tumors in children on the first place are hemoblastoses, then tumors of the brain and spinal cord, neuroblastoma, tumors of bones and soft tissues, kidneys, eyes, liver. It follows that most solid tumors are specific for children, whereas adults are found in very rare cases (Diagram 1).

Difficulties in diagnosing malignant neoplasms in children are explained not only by the rarity of these pathologies but also by the peculiarities of their clinical course: the prevalence of tumors of "hidden localizations," the set of "masks," which mask the manifestations of malignant tumors, the predominance of common symptoms in the clinical picture over local symptoms. The age of patients determines understandable difficulties in clarifying complaints and anamnesis of the disease.

#### 3. Primary tumor symptom complex

Common signs of malignant tumors appear in some cases earlier than local ones, they are united by the terms "primary tumor symptom complex" or "paraneoplastic syndrome" and although they are not specific, should alert the doctor and encourage him to make an in-depth examination of the patient to exclude or confirm malignant neoplasms [2].

Primary tumor symptom complex is a variety of pathological manifestations, caused by the indirect effect of the tumor process on the metabolism, immunity and functional activity of the body's regulatory systems.

Diagram 1. Structure of malignant tumors in children (%).

#### Clinical Manifestations and Diagnosis of Malignant Tumors in Children DOI: http://dx.doi.org/10.5772/intechopen.77362

Primary tumor symptom complex most often includes hypodynamia, lack of appetite, weight loss, lethargy, weakness, fatigue, capriciousness, anemia, subfebrile condition, and dermatitis.

These manifestations are caused by nonspecific reactions on the part of organs and systems or by ectopic production of a biologically active substance (hormones, proteins, growth factors, cytokines, antibodies), which causes a pathological increase in cell activity and forms certain manifestations, for example, Cushing's syndrome, fever, and erythrocytosis.

In the pathogenesis of the development of the primary tumor symptom complex, the response of the immune system is important in response to the presence of a tumor, an immunologically foreign antigen. This is the basis for the development of clinical symptoms of dermatomyositis, rheumatoid arthritis, autoimmune hemolytic anemia, and other systemic manifestations.

In some cases, the primary tumor symptom complex precedes the local symptoms of the tumor, whereas in others, it manifests simultaneously with them, sometimes will be added after the verification of the tumor process. The greatest difficulties arise in cases when the manifestations of the primary tumor symptom complex are treated as independent diseases or syndromes, which lead to the appointment of unjustified treatment and detection of malignant neoplasms at later stages.

Primary tumor symptom complex in the verification of malignant neoplasms is observed in 15% of patients, 50% of its manifestations develop during treatment, 35% in the late stages of the disease. Regression of the manifestations of the primary tumor symptom complex correlates with the tumor response to the therapy [2].

Leukemia is the most common tumor disease of childhood, which occurs mainly in the first 5–7 years of life. Among all leukemias in children, unlike adults, the vast majority (more than 95%) falls on acute forms.

Acute leukemias (AL) are clonal diseases that arise from a single mutated hematopoietic cell, which refers either to very early ones or to the cells of predecessors committed to different hematopoiesis lines. Thus, AL is a malignant tumor that originates from blast cells. The diagnosis of AL is established in the event that the number of blast cells in the bone marrow exceeds 25% [3].

AL in children of morphological origin is divided into acute lymphoblastic (80%) and acute nonlymphoblastic (20%) leukemia, which differ from each other both biologically and clinically, but in all cases, the clinical course is characterized by a high rate of increase in symptoms leading to rapid death of the patient [3, 4].

Clinical manifestations. In the clinical picture of AL, it is usually noted the presence of various symptomatic complexes, the most frequent among which are:

errors in diagnosis and, as a consequence, in treatment are connected. The patient's life depends, first of all, on the timely diagnosis, therefore, directly from the

In the structure of malignant tumors in children on the first place are