Genetic principles in paediatric surgery

GENETIC PRINCIPLES IN PAEDIATRIC SURGERY

Presented By:

Dr. Fariha Hussain Intern DoctorShaheed Suhrawardy Medical

College Hospital

Definition of Genetic Disorder Congenital Anomaly & Birth Defect

A Genetic Disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth.

A Congenital Anomaly is a physical abnormality present at birth.

Birth defects can be defined as structural or functional abnormalities, including metabolic disorders, which are present from birth

Note:

A genetic disorder may or may not result into a congenital anomaly

A congenital anomaly may or may not be caused by a genetic disorder

A congenital anomaly is a structural abnormality

A birth defect can be structural or functional

Studies have shown that:

1 to 3% of newborns have a major congenital anomaly that will affect their quality of life.

In 1988 Centres for Disease Control (CDC, USA) reported that birth defects were the leading cause of infant mortality, primary cause of infant deaths in 8160 children and contributing cause in 1000 more.

50% of all paediatric patients admitted in the hospital had a disorder with some genetic component.

Classification of Genetic Disorders

Multifactorial

Single gene (Mendelian)

Chromosomal

Mitochondrial

Somatic mutations (cancer)

Male

+ environment

Genetic Disorders

Multifactorial (common)- “Environmental” influences act on a genetic predisposition to produce a liability to a disease.- One organ system affected.- Person affected if liability above a threshold.

Single gene (1% liveborn) - Dominant/recessive pedigree patterns (Mendelian inheritance). - Can affect structural proteins, enzymes, receptors, transcription factors.

Chromosomal (0.6% liveborn)- Thousands of genes may be involved.- Multiple organ systems affected at multiple stages in gestation.- Usually de novo (trisomies, deletions, duplications) but can be inherited (translocations).

Recessive

Homozygotes with two copies of the altered gene are affected

Dominant

Heterozygotes with one copy of the altered gene are affected

X-linked recessive

Males with one copy of the altered gene on the X-chromosome are affected

Male

Congenital Malformations Causes

Genetic/chromosomal Environmental

Incidence 2-3% of newborn (4-6% by age 5) In 40-60% of all birth defects cause is

unknownGenetic/chromosomal

10%-15%Environmental

10%Multifactorial (genetic & environmental)

20%-25%

Birth Defects can be placed in one of the following established categories:

Categories of Birth Defects

Categories of Birth Defects:

DeformationDisruptionDysplasiaMalformationAssociationField DefectSequence

Deformation

Have no inherent genetic basis

Mechanical forces have altered the shape of the structure affected

Example: Talipes equinovarus or Clubfoot

Club Foot

Lower limbs were genetically programmed to form normally

External forces (e.g. decreased amount of amniotic fluid) or Internal forces (e.g. neurological impairment) prevented such development

Disruption

The genetic programme of the structure was normal like in Deformation

Developmental process was interrupted by some mechanism, causing the anomaly

Example: Anomalies in newborn exposed to cocaine in utero

Dysplasia

A generalized abnormality at the level of cellular organization in a specific tissue.

Example: Connective tissue disorder e.g. Marfan’s syndrome in which Fibrillin, a component of connective tissue is absent because of genetic mutation

Malformation

A malformation is an anomaly in which the developmental process was abnormal from the outset

Caused by: • Genetic Mutation• Congenital infection• Teratogen Exposure Example: Cleft lip & Palate

Cleft Lip and Palate

Structures that join the lip and palate fail to fuse normally

Syndrome

A child will have multiple malformations

The observed malformations are pathologically related to a single cause.

Example: - Down Syndrome - Turner’s Syndrome - Klinefelter’s Syndrome

A Child with Down Syndrome( Trisomy 21)

Features of Turner’s Syndrome (45XO)

Features of Klinefelter’s Syndrome (47XXY)

Association

An association is a nonrandom occurrence of a set of malformations that are not pathologically related

The malformations in Association occur more commonly together than separately

But not caused by the same genetic or teratogenic insult

Example: VACTERL Association CHARGE Association

VACTERL Association

Features V - Vertebral anomalies A - Anal atresia/

Imperforate Anus C - Cardiovascular

anomalies T - Tracheoesophageal

fistula E - Esophageal atresia R - Renal (Kidney)

and/or radial anomalies L - Limb defects

Newborn with radial atresia of the right arm, is displaying a limb anomaly included in VACTERL Association

CHARGE Association

Colobomas Heart defects Atresia of the

choanae

Retarded growthGenital anomoliesEar anomalies

 (A) Twin aged 2 months. (B) Twin aged 2 years showing mildly dysmorphic features with laterally extended eyebrows with medial flare. (C) A typical CHARGE ear, low set, short, wide, protruding, simplified, and featureless. The ears were also asymmetric.

Field Defect

A field defect is a set of malformations that are grouped in a localized area of body or a so called developmental field

An abnormal developmental stimuli e.g. a teratogen or mutated gene result in a developmental field defect

Example: Cloacal Extrophy

Cloacal Extrophy

Includes: Lower abdominal wall

defect Bladder extrophy Sacral vertebral

defects Urogenital anomaly Caused by abnormal

migration of neural crest cells in the caudal area in 4th week of gestation

Sequence

A series of findings that are derived from a single anomaly or mechanical force

Example : Pierre – Robin Sequence which results in Pierre- Robin’s Syndrome

Pierre – Robin Syndrome

Includes : Small Jaw A midline, U

shaped cleft palate

A relatively large and protruding tongue

Pierre – Robin Sequence

Small Jaw •Primary anomaly

Displacement of tongue in superior direction

•Protruding tongue due to inadequate room

Cleft Palate •Development of Pierre – Robin Syndrome from constellation of the three

Genetic Conditions Commonly Encountered in Paediatriac Surgical Wards

Spina Bifida Congenital

Diaphragmatic Defect

Duodenal Atresia Imperforate Anus Inguinal Hernia Hirschprung’s

Disease

Umbilical herniasClubfootOmphalocoelePyloric StenosisTracheoesophagial Fistula

Frequently occurring surgical anomalies with associated genetic conditions:

1. Congenital Diaphragmatic Defect: occurs in –

DiGeorge Syndrome Ehlers-Danlos Syndrome Marfan’s Syndrome Goldenhar Syndrome Turner’s syndrome Trisomy 13, 18, 21

2. Duodenal Atresia : Down’s Syndrome Fetal Hydantoin

Exposure Thalidomide Exposure Opitz Syndrome

3. Hirschprung’s Disease: Cartilage- hair hypoplasia Down’s Syndrome Multiple Endocrine

Adenomatosis type3 Pallister – Hall Syndrome Spondylometaphysial Dysplasia

4. Imperforate Anus: Baller- Gerold Syndrome Cat’s Eye Syndrome FG Syndrome Opitz Syndrome Johanson-Blizzard Syndrome VACTERL Association

5. Inguinal Hernia: Cutis- Laxa Syndrome Ehlers Danlos Syndrome Marfan’s Syndrome

6. Omphalocele: Cloacal Extrophy Syndrome Marshall-Smith Syndrome Meckel-Gruber Syndrome Sirenomelia Skeletal Dysplasias

7. Pyloric Stenosis:Apert SyndromeCornelia de Lange SyndromeFetal Hydantoin EffectsFetal Trimethadione effectsTrisomy 18, 21

8. Tracheoesophagial Fistula: CHARGE associationDiGeorge SyndromeOpitz SyndromeVACTERL associationTrisomy 18, 21

Assessment of the child with a congenital anomaly

A collaborative effort among many physicians including a clinical geneticist is required

Seemingly unrelated problems has to be unified under one diagnostic heading

In planning appropriate therapy, a surgeon needs to know the prognosis of certain genetic disorders

The initial assessment needs to address certain key points:

1. Are other organ systems involved? And if so, what are the associated anomalies?

2. What are the child’s growth parameters, including height, weight and head circumference?

3. Is the child neurologically intact or is there evidence of developmental delay or mental retardation?

4. Are there abnormal features present e.g. widely spaced eyes, low set ears or a small jaw?

Availavble Tools for the Diagnosis of a Child with Birth Defects

Clinical Evaluation: Associated anomalies Neurologic examinations Dysmorphology (Study of abnormal forms)

evaluation Dermatoglyphics (Fingerprint pattern)

Pedigree Analysis Literature Search Specialized Laboratory Tests:

Radiography, USG, MRI Chromosome analysis Molecular tests Metabolic tests

Prevention and Treatment OptionsBirth Defects can be prevented by:

Pre-conceptional care & Increasing Folic Acid Intake

Limiting Exposure to Teratogens and Mutagens:Alcohol & Certain drugsRadiationTobaccoCigarette

Infection screening during pregnancy Genetic Testing During Pregnancy

AmniocentesisChorionic villus sampling

Genetic Counselling of the parents

Treatment options for a child with Genetic Birth Defect: Mostly surgical correction of the defect:

Early surgery on the fetus in utero Surgical correction after birth

Other treatments: Medical treatment of the associated

problems Palliative care (e.g. in case of

Anencephaly) Termination of pregnancy in case of

severe birth defects

Conclusion

Of course, many birth defects cannot be prevented; this is especially true of defects that have a genetic component. Thankfully, screening and treatment methods can be implemented to avoid the complications of birth defects and increase an affected child's possibilities of a better quality of life.