Presented By:Dr. Fariha HussainIntern 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
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 + environment Single gene (Mendelian) Male Chromosomal Mitochondrial Somatic mutations (cancer)
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).
Dominant Heterozygotes with one copy of the altered gene are affected Recessive Homozygotes with two copies of the altered gene are affected X-linked recessive Males with one copy of the altered gene on the X-chromosome are affectedMale
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 unknown Genetic/chromosomal 10%-15% Environmental 10% Multifactorial (genetic & environmental) 20%-25%
Categories of Birth DefectsBirth Defects can be placedin one of the followingestablished categories:
Categories of Birth Defects: Deformation Disruption Dysplasia Malformation Association Field Defect Sequence
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
Cocaine (Vasoconstrictive agent)Temporarily restrictied blood suply to the developing structures Malformations Craniofacial anomalies, Intestinal Atresia etc.
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
MalformationA 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
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 Newborn with radial atresia of the R - Renal (Kidney) right arm, is displaying a limb and/or radial anomalies anomaly included in VACTERL Association L - Limb defects
CHARGE Association Colobomas Retarded growth Heart defects Genital anomolies Atresia of the Ear anomalies choanae (A) Twin aged 2 months. (B) Twin aged 2 years showing mildlydysmorphic features with laterally extended eyebrows with medial flare. (C)A typical CHARGE ear, low set, short, wide, protruding, simplified, andfeatureless. 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
SequenceA series of findings that are derived from a single anomaly or mechanical forceExample : Pierre – Robin Sequence which results in Pierre- Robin’s Syndrome
Pierre – Robin SyndromeIncludes : Small Jaw A midline, U shaped cleft palate A relatively large and protruding tongue
Pierre – Robin Sequence Small • Primary anomaly JawDisplaceme • Protruding tongue due to nt of tongue in inadequate room superior direction • Development of Pierre – Cleft Robin Syndrome from Palate constellation of the three
7. Pyloric Stenosis: Apert Syndrome Cornelia de Lange Syndrome Fetal Hydantoin Effects Fetal Trimethadione effects Trisomy 18, 21
8. Tracheoesophagial Fistula: CHARGE association DiGeorge Syndrome Opitz Syndrome VACTERL association Trisomy 18, 21
Assessment of the child with acongenital 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.
Availavble Tools for the Diagnosisof 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
Prevention and TreatmentOptionsBirth Defects can be prevented by: Pre-conceptional care & Increasing Folic Acid Intake Limiting Exposure to Teratogens and Mutagens: Alcohol & Certain drugs Radiation Tobacco Cigarette Infection screening during pregnancy Genetic Testing During Pregnancy Amniocentesis Chorionic 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 childs possibilities of a better quality of life.