**2. Abnormal morphogenesis**

Normal morphogenesis is a systematic process that involves a combination of several simultaneously or sequentially occurring histo-physiological activities at the cellular and molecular levels. These processes are cell migration, aggregation of identical cell types, the interaction between neighboring tissues, controlled cell death, mechanical forces, and hormonal effects. The congenital anomaly is an outcome of abnormal morphogenesis and is defined as any structural or functional anomaly detected at birth that interferes with the performance or appearance of the subject. The etiopathogenesis of congenital anomalies is broadly divided into genetic and non-genetic groups, and the latter one is classified into several major sub-categories. Some anomalies remain idiopathic in etiopathogenesis, and others may be multifactorial, i.e., have both genetic and environmental influences. Congenital anomalies are categorized as major and minor as per their clinical implications. While major anomalies have significant adverse medical consequences, minor malformations may be of cosmetic significance only. The prevalence of major malformations is reported to range from 2 to 4 percent according to the population studied, while minor anomalies may be as high as 35% in certain populations [5]. The presence of 3 or more minor malformations is associated with an increased risk of a major anomaly or syndrome. Major anomalies are generally the consequence of molecular defects that interfere with normal morphogenesis processes like apoptosis, intracellular signaling, migration of neural crest derivatives, and chromatin remodeling. Some of the genes (e,g. Homeobox genes in Synpolydactyly, microphthalmia, and holoprosencephaly), transcription factors (e.g., deletions of T-box 1 in Conotruncal heart defects of DiGeorge syndrome), fibroblast growth factor receptors (in Craniosynostoses syndromes), and enzyme defects (such as cholesterol biosynthesis leading to Smith-Lemli-Opitz syndrome) have been identified as etiopathogenic factors for specific major malformations.

#### **2.1 Patterns of abnormal phenotypes**

Abnormal morphogenesis may manifest in various forms at the macroscopic and microscopic levels [6]. Following are some of the common patterns and terminologies used in the description of an abnormal phenotype.

• Anomaly is defined as a significant morphological or anatomic variation in the phenotype from the standard reference population. The difference may be macroscopic or microscopic. Anomalies are categorized into major and minor. Major anomalies have significant adverse implications in functional, anatomical, psychological, social, or cosmetic wellbeing, and minor anomalies are variants with no significant medical or major cosmetic consequences. The presence of three or more minor anomalies suggests significant defects in morphogenesis. Even though detected in only 0.5% of births, almost 90% of such cases have ≥1 major anomaly and might eventually end up with the diagnosis of some associations or syndrome.

**3**

**Figure 2.**

*Introductory Chapter: Epidemiology, Evaluation and Risk Assessment of Congenital Anomalies*

• Malformation is an inherently non-progressive morphologic anomaly brought about primarily by an intrinsic error in the developmental process at the cellular or molecular levels of an organ or a body part. Malformations may be isolated, or part of a syndrome and are causally heterogeneous. The aberration can happen due to gene mutations, exposure to teratogens, or a combination of the two. For example, the limb anomaly in Holt–Oram syndrome is genetic in origin, whereas in thalidomide embryopathy, it is due to teratogenic exposure.

• Deformation alludes to a distortion of the shape or size in an otherwise normal body part of a normally developing or developed fetus, caused by some aberrant extrinsic or intrinsic mechanical forces. Examples include craniofacial asymmetry, arthrogryposis, and metatarsus adductus (**Figure 2**). Uterine anomalies and abnormal fetal positions are important setups for the generation of fetal deformation. Deformations are causally heterogeneous and may result in the loss of alignment or abnormal positioning and distorted configuration. Deformations are generally reversible after birth but may be difficult if the transduction of abnormal mechanical forces is prolonged. Deformation generally happens after organogenesis, but if in early gestation, it may permanently alter the structural relationships. If mechanical transduction happens during embryogenesis, anomalies in the neural tube, tendons, and joints may be

• Disruption is defined as a static morphologic abnormality brought about in-utero by some destructive mechanical forces acting upon an otherwise normally developing or developed fetal tissue or physical part. It results in the destruction of the involved body part and may cause the developmental arrest of the adjacent tissues, thereby leading to a secondary malformation (**Figure 3**). It can be an initial event in a sequence of events if it occurs early in gestation. It is causally heterogeneous and may be isolated or part of a syndrome or other broader patterns. A disruption can impart a particularly distinctive appearance because of the loss of tissue and aberrant differentiation of adjacent tissues with or without the production of adhesions. The process results in cell death and tissue destruction, and the mechanisms may include vascular compromise, anoxia, teratogens exposure, infections, or mechanical forces. Clinical entities such as missing digits or limbs are examples of disruption. The process

*Metatarsus adductus as an example of deformation due to intrauterine positioning or space constraints.*

*DOI: http://dx.doi.org/10.5772/intechopen.97181*

produced.

*Introductory Chapter: Epidemiology, Evaluation and Risk Assessment of Congenital Anomalies DOI: http://dx.doi.org/10.5772/intechopen.97181*


*Congenital Anomalies in Newborn Infants - Clinical and Etiopathological Perspectives*

**2. Abnormal morphogenesis**

etiopathogenic factors for specific major malformations.

gies used in the description of an abnormal phenotype.

Abnormal morphogenesis may manifest in various forms at the macroscopic and microscopic levels [6]. Following are some of the common patterns and terminolo-

• Anomaly is defined as a significant morphological or anatomic variation in the phenotype from the standard reference population. The difference may be macroscopic or microscopic. Anomalies are categorized into major and minor. Major anomalies have significant adverse implications in functional, anatomical, psychological, social, or cosmetic wellbeing, and minor anomalies are variants with no significant medical or major cosmetic consequences. The presence of three or more minor anomalies suggests significant defects in morphogenesis. Even though detected in only 0.5% of births, almost 90% of such cases have ≥1 major anomaly and might eventually end up with the diagnosis

**2.1 Patterns of abnormal phenotypes**

of some associations or syndrome.

other childhood morbidity. While 3.0% of all hospitalizations are attributed to birth anomalies, the diagnosis accounts for 5.2% of total hospital costs. The cost of care is highest in the children who are <1 year of age and accounts for 35.0% of the total hospitalization costs among the pediatric population. The congenital cardiac defects register the highest CA-associated hospitalization costs across all age groups at 26.6%, while only 14.0% of CA–associated hospitalizations are attributed to this system.

Normal morphogenesis is a systematic process that involves a combination of several simultaneously or sequentially occurring histo-physiological activities at the cellular and molecular levels. These processes are cell migration, aggregation of identical cell types, the interaction between neighboring tissues, controlled cell death, mechanical forces, and hormonal effects. The congenital anomaly is an outcome of abnormal morphogenesis and is defined as any structural or functional anomaly detected at birth that interferes with the performance or appearance of the subject. The etiopathogenesis of congenital anomalies is broadly divided into genetic and non-genetic groups, and the latter one is classified into several major sub-categories. Some anomalies remain idiopathic in etiopathogenesis, and others may be multifactorial, i.e., have both genetic and environmental influences. Congenital anomalies are categorized as major and minor as per their clinical implications. While major anomalies have significant adverse medical consequences, minor malformations may be of cosmetic significance only. The prevalence of major malformations is reported to range from 2 to 4 percent according to the population studied, while minor anomalies may be as high as 35% in certain populations [5]. The presence of 3 or more minor malformations is associated with an increased risk of a major anomaly or syndrome. Major anomalies are generally the consequence of molecular defects that interfere with normal morphogenesis processes like apoptosis, intracellular signaling, migration of neural crest derivatives, and chromatin remodeling. Some of the genes (e,g. Homeobox genes in Synpolydactyly, microphthalmia, and holoprosencephaly), transcription factors (e.g., deletions of T-box 1 in Conotruncal heart defects of DiGeorge syndrome), fibroblast growth factor receptors (in Craniosynostoses syndromes), and enzyme defects (such as cholesterol biosynthesis leading to Smith-Lemli-Opitz syndrome) have been identified as

**2**

**Figure 3.** *Amputation of digits with a constricting amniotic band as an example of disruption.*

characteristically affects several tissue types in a specific anatomical region, and the phenotypic abnormalities may cross cell lines of embryonic development. Some pathological developmental processes can cause both disruption and deformation. For example, constriction rings at the tip of a finger associated with bands (fibrous strands of tissue) are often used as an example of disruption, but fibrous bands can also cause deformation. "Amniotic bands" encircling a limb are one possible mechanism of disruption of an extremity.


**5**

*Introductory Chapter: Epidemiology, Evaluation and Risk Assessment of Congenital Anomalies*

chance only. Some associations may be syndromes with overlapping features. Such cases may eventually be identified to have a pathological etiology and then moved to the category of a syndrome. In the case of CHARGE association, after the causative gene was identified, the nomenclature was changed to

• A syndrome is a combination of causally but not necessarily pathogenically related anomalies that are characterized into a specific condition. The anomalies can be malformations, deformations, disruptions, sequences or dysplasia, major or minor, or functional, such as those affecting the neurological, cogni-

Genetically determined and inheritable diseases can occur as a result of chromosomal or single-gene (Mendelian) abnormalities. Some of the inherited disorders are multifactorial in origin, and others may be attributed to defects in the mitochondrial chromosomes [7]. The last category has the highest phenotypic variability due to heteroplasmy and the fact that mitochondrial DNA has high incidence of mutation [8]. As the mitochondrial DNA is inherited from the mother, the genetic transmission occurs from the affected mother only. Single gene disorders (SGD) may present with autosomal dominant, autosomal recessive, X-linked recessive, and X-linked dominant patterns of inheritance. Cystic fibrosis is the commonest SGD

Chromosomal anomalies may result from maldistribution (numerical aberrations) or rearrangements (structural abnormalities) of chromosomes. A numerical error in the array of chromosomes is termed aneuploidy, which presents as polyploidy with an addition or monosomy with a reduction in the number of chromosomes (**Figure 4**). Most of these conditions result from the failure of chromosomes to disjoin during meiosis (non-disjunction). Some of the common examples of aneuploidy are the trisomy syndromes or Turner and Klinefelter

Structural chromosome disorders result from the breakage and rearrangement

• Deletion refers to the loss of a piece or section of chromosomal material. If too small to be visualized under a microscope, it is termed microdeletion. Deletions can be terminal if only one break is present at the end or interstitial if two pieces of chromosome material are lost from within the chromosome. There is only one copy of a particular chromosome segment instead of the

• Duplication presents with an extra copy of a segment of a chromosome. So there are three copies of a particular chromosome segment instead of the

• Mutation indicates a change in the DNA sequence that leads to a change in its function. A mutation may be silent (no overt clinical signs or symptoms as amino acids may be encoded on different codons); missense (the codon is changed by a new nucleotide); nonsense (new nucleotide changes the codon to a STOP codon so that the mRNA translation is stopped) or splice-site when

mutation at splice site prevents removal of an intron.

*DOI: http://dx.doi.org/10.5772/intechopen.97181*

tive, sensory, or behavioral performances.

CHARGE syndrome.

**2.2 Anomalies of genotype**

reported in the Caucasian population.

of segments or parts of a chromosome (**Figure 5**).

usual two copies in deletion syndromes.

syndromes.

usual two.

*Introductory Chapter: Epidemiology, Evaluation and Risk Assessment of Congenital Anomalies DOI: http://dx.doi.org/10.5772/intechopen.97181*

chance only. Some associations may be syndromes with overlapping features. Such cases may eventually be identified to have a pathological etiology and then moved to the category of a syndrome. In the case of CHARGE association, after the causative gene was identified, the nomenclature was changed to CHARGE syndrome.

• A syndrome is a combination of causally but not necessarily pathogenically related anomalies that are characterized into a specific condition. The anomalies can be malformations, deformations, disruptions, sequences or dysplasia, major or minor, or functional, such as those affecting the neurological, cognitive, sensory, or behavioral performances.

#### **2.2 Anomalies of genotype**

*Congenital Anomalies in Newborn Infants - Clinical and Etiopathological Perspectives*

characteristically affects several tissue types in a specific anatomical region, and the phenotypic abnormalities may cross cell lines of embryonic development. Some pathological developmental processes can cause both disruption and deformation. For example, constriction rings at the tip of a finger associated with bands (fibrous strands of tissue) are often used as an example of disruption, but fibrous bands can also cause deformation. "Amniotic bands" encircling

a limb are one possible mechanism of disruption of an extremity.

*Amputation of digits with a constricting amniotic band as an example of disruption.*

• Dysplasia is an abnormality in the growth and development of cell or tissue histology, or the anatomical structure or physiological function resulting from such growth. Tumors and malignancies are the results of a dysplasia process. Dysplasia can be isolated in occurrence or be a part of broader patterns. Dysplasias are causally heterogeneous and can be triggered by genetic factors, teratogens exposure, or metabolic disorders. The presentation may involve one or multiple germ layers and single or multiple organs. It may be localized or generalized; unilateral or bilateral; focal or multifocal; benign, malignant or premalignant; static or progressive; or evanescent. Dysplasia may be associated with malformations. It can happen at the cellular level (microscopic), examples being BPD and fibrous epithelial dysplasia, or in organs (macroscopic) such as renal dysplasia. It may be a dynamic or an ongoing process and maybe widespread or confined to a single organ. It can occur both prenatally and

• Sequence refers to the phenomenon of a single or multiple morphological anomalies cascading from a single primary anomaly, which might be malformation, disruption, dysplasia, or deformation in character. The resultant anomaly is not an essential and direct derivation of the primary cause, as happens in genetic aberration cases. A sequence can occur as an isolated phenomenon or as a component manifestation of broader patterns such as syndromes; and like malformations is causally heterogeneous. A common example is the Pierre Robin sequence, in which a small mandible, the primary anatomical defect, leads to protruding tongue, which in turn may interfere with the palatal closure and consequently create a cleft palate. In describing a sequence, sometimes it may be difficult to distinguish between the primary

• Association is defined as a pattern of morphological anomalies which are not causally related but occur together more often than would be expected by

**4**

postnatally.

**Figure 3.**

and the consequential effects.

Genetically determined and inheritable diseases can occur as a result of chromosomal or single-gene (Mendelian) abnormalities. Some of the inherited disorders are multifactorial in origin, and others may be attributed to defects in the mitochondrial chromosomes [7]. The last category has the highest phenotypic variability due to heteroplasmy and the fact that mitochondrial DNA has high incidence of mutation [8]. As the mitochondrial DNA is inherited from the mother, the genetic transmission occurs from the affected mother only. Single gene disorders (SGD) may present with autosomal dominant, autosomal recessive, X-linked recessive, and X-linked dominant patterns of inheritance. Cystic fibrosis is the commonest SGD reported in the Caucasian population.

Chromosomal anomalies may result from maldistribution (numerical aberrations) or rearrangements (structural abnormalities) of chromosomes. A numerical error in the array of chromosomes is termed aneuploidy, which presents as polyploidy with an addition or monosomy with a reduction in the number of chromosomes (**Figure 4**). Most of these conditions result from the failure of chromosomes to disjoin during meiosis (non-disjunction). Some of the common examples of aneuploidy are the trisomy syndromes or Turner and Klinefelter syndromes.

Structural chromosome disorders result from the breakage and rearrangement of segments or parts of a chromosome (**Figure 5**).


#### **Figure 4.**

*An example of aneuploidy with Trisomy 21 showing an extra chromosome 21.*

#### **Figure 5.**

*Common structural chromosomal anomalies resulting in abnormal genotype.*


**7**

*Introductory Chapter: Epidemiology, Evaluation and Risk Assessment of Congenital Anomalies*

• Isochromosomes result from abnormal mitosis in which a break at centromere results in two short (p) arms or two long (q) arms from the same side, both

• Dicentric chromosomes are defined as the abnormal fusion of two chromo-

• Ring chromosomes form when the deletion happens at the ends of both arms of the same chromosome and the remaining chromosome join, making a ring-like shape. The chromosomes may be eventually lost, resulting in

The clinical evaluation of a child born with an anomaly begins with a detailed

The physical examination starts with the standard measurements of weight, length, and head circumference. In infants suffering from short stature, skeletal dysplasia, or suspected Marfan syndrome, arm span and lower segment/upper segment ratio are useful variables to note. The following is a list of specific features and characteristics to seek during the general evaluation of an infant with congenital malformations: midface hypoplasia; prognathism , retrognathia, micrognathia; facial asymmetry; hypertelorism, hypotelorism; ophthalmoplegia; esotropia, exotropia; cataract; nystagmus; ptosis; inner canthal distance, outer canthal distance, interpupillary distance; palpebral fissures length; long, anteriorly or posteriorly rotated ears; low set ears; microtia; prominent, bulbous nasal tip; slit appearance of nose; anteverted nares; long or smooth philtrum; macrostomia, microstomia, high arched palate, cleft lip/palate; cleft uvula,; macroglossia, protruding tongue ; wide or short neck , neck webbing ; pectus excavatum or pectus carinatum; wide-spaced nipples; scoliosis, deep sacral dimple, sacral hair tuft, sacral tag; sirenomelia; limited range of motion of extremities, contracture; polydactyly syndactyly, brachydactyly, arachnodactyly, broad thumbs and toes; clubfoot; breast development; Tanner staging. Ambiguous genitalia; micropenis; cryptorchidism; hypoplasia of labia or vaginal hypoplasia/atresia, sparse or excess body hair; abnormally light hair; skin hyperpigmentation /hypopigmentation; albinism; nail dystrophy. In addition to these, a detailed systemic evaluation is an essential and integral part of the physical examination of a child born with anomalies. The physical examination should be

history of the extended family and a comprehensive history of the parents, with special attention to age, gravidity, parity, miscarriages, pregnancy-related complications, history of prescription drugs intake, substance abuse, significant illnesses and consanguinity among others. This is followed by a thorough physical examination, which should consist of a detailed assessment of craniofacial profile for dysmorphology and of individual organ systems, including the vertebral column, extremities, and skin. The histopathological features of the placenta and umbilical cord should be noted. The next step includes the performance of specific diagnostic tests, which are selected on the basis of the results of history and physical findings and should be individualized according to the case. Referral to a geneticist is indicated if one major or more than two minor

**3. Evaluation of an infant with congenital malformations**

standardized and performed by a trained dysmorphologist [9].

*DOI: http://dx.doi.org/10.5772/intechopen.97181*

some pieces, both having a centromere.

carrying identical genes.

monosomy.

anomalies are present.

**3.1 Physical examination**

*Introductory Chapter: Epidemiology, Evaluation and Risk Assessment of Congenital Anomalies DOI: http://dx.doi.org/10.5772/intechopen.97181*

