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

The clinical evaluation of a child born with an anomaly begins with a detailed 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 anomalies are present.

#### **3.1 Physical examination**

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

**6**

**Figure 5.**

**Figure 4.**

*Common structural chromosomal anomalies resulting in abnormal genotype.*

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

• Translocation happens when genetic material is exchanged between two chromosomes. It may be balanced with no gain or loss of DNA and no anomalies or unbalanced when the process results in gain or loss of chromosomal material. Even though there may not be any phenotypical anomalies, balanced transloca-

tions might have implications for the offsprings of the patient.

• Reciprocal translocation is an anomaly in which the phenotype is normal despite the break and exchange of material between 2 chromosomes.

anomaly, the short arm is lost, and long arms fuse at the centromere.

• Robertsonian translocation is another example in which the phenotype may be normal. It involves only selected chromosomes, such as 13,14,15,21,22. In this

• Inversion is described when a piece of a chromosome breaks at two places and then is reinserted in the opposite direction. Inversions may be paracentric if it does not involve centromere or pericentric if the centromere is involved.

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 standardized and performed by a trained dysmorphologist [9].

#### **3.2 Specific tests and laboratory investigations**

As mentioned earlier, the need and selection of testing depend upon the results of the history and physical examination. Specific tests commonly include computed tomography (CT), and magnetic resonance imaging (MRI) scans of the central nervous system (CNS), echocardiogram, skeletal survey, and autopsy if the patient expires. An ultrasound evaluation of the genitourinary system is indicated in the conditions of ambiguous genitalia in order to detect the presence of abdominal gonads and uterus and to assess the anatomy of kidneys, ureters, bladder, and testicles. Fundoscopy may be done to detect ocular anomalies, such as retinal colobomas, optic disc defects, and chorioretinitis. TORCH infections and other significant viral infections should be ruled out by performing specific tests as clinically indicated.

#### **3.3 Tests for suspected genetic disorders**

The selection of chromosomal studies is guided by the clinical presentation. Exome sequencing helps in the identification of rare single-gene disorders and is indicated in the conditions of multiple, complex congenital anomalies with no otherwise identified genetic defect. Molecular-based chromosome microarray studies (array comparative genomic hybridization or aCGH) are utilized to diagnose microdeletions. aCGH is the first line of testing in children with multiple anomalies and intellectual disabilities [10]. It has now replaced Giemsa banding karyotype (G-banding) and fluorescent in situ hybridization (FISH) studies. aCGH testing may be indicated in the following conditions: one or more major anomalies, three or more minor anomalies, unexplained intellectual deficiency, dysmorphism with or without tone and intellectual deficits, unexplained failure to thrive, family history of birth defects, and multiple miscarriages [11]. The FISH test may be used to confirm a microdeletion or microduplication detected by aCGH and is generally used in the prenatal screening of cells in amniotic fluid. In the conditions of consanguinity or suspected uniparental disomy (UPD), where the chromosome material is coming from one parent only, single nucleotide polymorphisms (SNPs) is indicated. Another test, called Whole-exome sequencing (WES), is used in children with multiple structural anomalies associated with intellectual disability and/or seizures [12]. This technique uses next-generation sequencing and can simultaneously analyze the coding regions of almost 19,000 to 20,000 genes. While WES cannot be used for the detection of microdeletions or microduplications, whole-genome sequencing (WGS) can detect larger deletions or duplications, as well as triple repeat expansions; and mutations in deep intronic regions, regulatory regions that are outside of the coding regions, and untranslated gene regions.

Some genetic disorders are metabolic in origin and require metabolic studies in addition to the genetic workup. These studies include tests for blood amino acids and urine organic acids, specific tests for the peroxisomal disorder, including liver biopsy in certain conditions, assessment of serum cholesterol precursors, and lactic acid and pyruvic acid levels in the blood and cerebrospinal fluid, among others. Metabolomics uses mass spectrometry to detect and quantify small molecules in plasma for the diagnosis of inborn errors of metabolism. This procedure scientifically studies the small molecule substrates (<1.5 kDa) called metabolites which are products of the biochemical processes in cellular metabolism. One of the cellular functions that entails mRNA, gene expression, and proteomic analyses leads to the release of gene products in the cell. Metabolomics meets the challenge of systems biology and functional genomics by integrating genomics, transcriptomic and proteomic information. Thus metabolomic information provides a better understanding of cellular biology.

**9**

**Table 1.**

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

life. The quality of life also is widely variable depending on the disorder.

**Disease Condition Recurrence risk**

Cleft lip Unaffected parents, 1 child affected 4.5% risk for next child

Cardiac defects 1 child affected 3.4% risk for next child

Neural tube defects 1 child affected 3.5% risk to next child Trisomy 21 Mother with balanced translocation 10–15% risk for sibling

1 child affected, no parental

Hirschsprung's disease 1 child affected 3–5% risk for next child

Club foot 1 affected child 2% risk if 1st child is male, 5% if

*Recurrence risk of certain malformations. (adapted from Jones KL, Smiths recognizable patterns of human malformations, 5th edition, WB Saunders, Philadelphia, 1997; and Neonatology Review, 2nd edition,* 

translocation

*D. Brodsky & C. Martin, Hanley and Belfus Inc.2003.*

Cleft palate 1 child affected 2.6% risk to sibling

**4. Risk assessment of congenital anomalies**

The clinical care of a child is done via a multi-disciplinary approach and involves a team of pediatrician, geneticist, neurologist, cardiologist, surgeon, orthopedics surgeon, dermatologist, infectious disease specialist, and other specialties as indicated. The involvement of the social worker is important for family and social support. The natural course, complications, and eventual clinical outcomes depend on the anomaly and may range from inconsequential to severe. Some CAs are lethal in nature. Death from lethal anomalies can occur in-utero, at birth, during the perinatal period, or later at various stages of life. Others may have a normal span of

The assessment of risks for CA may not always be possible due to the lack of referable evidence and information. The known recurrence risks of some of the heritable disorders are presented in **Table 1**. Some of the risk factors for CA are well documented, such as parental age, subjects' gender, geographical location and exposure to drugs or toxins etc. Advanced maternal age is extensively reported to be associated with aneuploidies, such as trisomy 21, 13, and 18 and Klinefelter syndrome. Advanced maternal age has also been associated with non-chromosomal genitourinary anomalies,

Pyloric stenosis Mother affected 19% risk for male, 7% for female

Congenital hip dysplasia 1 affected child 0.5% risk for male 6.3% for female

offspring

child

1% risk for sibling

female

Father affected 5.5% risk for male, 2.4% for female 1 child affected 4% risk to next male 2.4% to female child

1 parent and 1 child affected 10% risk to next child

2 children affected 10% risk for next child

Father with balanced translocation 5% risk for sibling

1 parent and 1 child affected 25% risk to next child

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

**3.4 Clinical care and outcome**

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

### **3.4 Clinical care and outcome**

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

As mentioned earlier, the need and selection of testing depend upon the results of the history and physical examination. Specific tests commonly include computed tomography (CT), and magnetic resonance imaging (MRI) scans of the central nervous system (CNS), echocardiogram, skeletal survey, and autopsy if the patient expires. An ultrasound evaluation of the genitourinary system is indicated in the conditions of ambiguous genitalia in order to detect the presence of abdominal gonads and uterus and to assess the anatomy of kidneys, ureters, bladder, and testicles. Fundoscopy may be done to detect ocular anomalies, such as retinal colobomas, optic disc defects, and chorioretinitis. TORCH infections and other significant viral infections should be ruled out by performing specific tests as

The selection of chromosomal studies is guided by the clinical presentation. Exome sequencing helps in the identification of rare single-gene disorders and is indicated in the conditions of multiple, complex congenital anomalies with no otherwise identified genetic defect. Molecular-based chromosome microarray studies (array comparative genomic hybridization or aCGH) are utilized to diagnose microdeletions. aCGH is the first line of testing in children with multiple anomalies and intellectual disabilities [10]. It has now replaced Giemsa banding karyotype (G-banding) and fluorescent in situ hybridization (FISH) studies. aCGH testing may be indicated in the following conditions: one or more major anomalies, three or more minor anomalies, unexplained intellectual deficiency, dysmorphism with or without tone and intellectual deficits, unexplained failure to thrive, family history of birth defects, and multiple miscarriages [11]. The FISH test may be used to confirm a microdeletion or microduplication detected by aCGH and is generally used in the prenatal screening of cells in amniotic fluid. In the conditions of consanguinity or suspected uniparental disomy (UPD), where the chromosome material is coming from one parent only, single nucleotide polymorphisms (SNPs) is indicated. Another test, called Whole-exome sequencing (WES), is used in children with multiple structural anomalies associated with intellectual disability and/or seizures [12]. This technique uses next-generation sequencing and can simultaneously analyze the coding regions of almost 19,000 to 20,000 genes. While WES cannot be used for the detection of microdeletions or microduplications, whole-genome sequencing (WGS) can detect larger deletions or duplications, as well as triple repeat expansions; and mutations in deep intronic regions, regulatory regions that

are outside of the coding regions, and untranslated gene regions.

Some genetic disorders are metabolic in origin and require metabolic studies in addition to the genetic workup. These studies include tests for blood amino acids and urine organic acids, specific tests for the peroxisomal disorder, including liver biopsy in certain conditions, assessment of serum cholesterol precursors, and lactic acid and pyruvic acid levels in the blood and cerebrospinal fluid, among others. Metabolomics uses mass spectrometry to detect and quantify small molecules in plasma for the diagnosis of inborn errors of metabolism. This procedure scientifically studies the small molecule substrates (<1.5 kDa) called metabolites which are products of the biochemical processes in cellular metabolism. One of the cellular functions that entails mRNA, gene expression, and proteomic analyses leads to the release of gene products in the cell. Metabolomics meets the challenge of systems biology and functional genomics by integrating genomics, transcriptomic and proteomic information. Thus metabolomic information provides a better understanding of cellular biology.

**3.2 Specific tests and laboratory investigations**

**3.3 Tests for suspected genetic disorders**

clinically indicated.

**8**

The clinical care of a child is done via a multi-disciplinary approach and involves a team of pediatrician, geneticist, neurologist, cardiologist, surgeon, orthopedics surgeon, dermatologist, infectious disease specialist, and other specialties as indicated. The involvement of the social worker is important for family and social support. The natural course, complications, and eventual clinical outcomes depend on the anomaly and may range from inconsequential to severe. Some CAs are lethal in nature. Death from lethal anomalies can occur in-utero, at birth, during the perinatal period, or later at various stages of life. Others may have a normal span of life. The quality of life also is widely variable depending on the disorder.
