Congenital Defects, Genetic and Chromosomal Disorders

Congenital Defects Overview

Congenital defects are structural, functional, or metabolic abnormalities present at birth, significantly contributing to infant mortality. Causes include genetic and environmental factors.

Genetic and Chromosomal Disorders

Genetic disorders often stem from DNA sequence changes, impacting single-gene products, or from chromosomal aberrations like deletions, duplications, or abnormal chromosome numbers. Alleles are gene pair members; identical alleles define a homozygous state, while different alleles define a heterozygous state. Genotype refers to a person's genetic composition, and phenotype, its observable expression.

Single-Gene Disorders

Caused by a mutant allele at a single-gene locus, following Mendelian inheritance patterns. These disorders result in abnormal protein formation or decreased gene product production. Examples include autosomal dominant, autosomal recessive, and X-linked recessive disorders.

Autosomal Dominant Disorders

A single mutant allele from an affected parent is transmitted to offspring with a 50% chance. Reduced penetrance and variable expressivity can occur.

Marfan Syndrome

Autosomal dominant connective tissue disorder affecting fibrillin I (FBNI gene on chromosome 15q21), impacting the eyes, cardiovascular system, and skeleton, leading to abnormalities and potential cardiovascular risks.

Neurofibromatosis (NF)

Causes tumors from Schwann cells; includes NF-1 and NF-2, both from genetic defects in tumor suppressor genes regulating cell growth. Type 1 (NF-1) involves neurofibromas and pigmentations, while Type 2 (NF-2) involves acoustic nerve tumors.

Autosomal Recessive Disorders

Manifest only when both gene pair alleles are affected (homozygous). Parents are typically unaffected carriers. Each pregnancy has a 25% risk of an affected child. These disorders often involve loss-of-function mutations, impairing enzyme function (e.g., PKU, Tay-Sachs).

Phenylketonuria (PKU)

Deficiency in phenylalanine hydroxylase, leading to toxic phenylalanine levels, causing intellectual disability if untreated. Managed with a special diet.

Tay-Sachs Disease

Lysosomal storage disease due to failure to break down GM2 gangliosides, leading to rapid motor and mental deterioration in infants, more common in Ashkenazi Jews.

X-Linked Recessive Disorders

Associated with the X chromosome, more common in males. Affected males inherit the gene from carrier mothers, while carrier females are rarely affected due to a normal X chromosome.

X-Linked Dominant Disorders

Less common; affect both males and females. Often, the mutation is embryonic lethal for males or homozygous mutant females. Examples include fragile X syndrome and Rett syndrome.

Fragile X Syndrome

Single-gene disorder causing intellectual disability due to CGG repeat amplification on the Xq27 site of the FXTR1 gene, leading to no FXP production.

Inherited Multifactorial Disorders

Involve multiple genes and environmental factors. They include congenital conditions (cleft lip/palate, clubfoot, congenital heart disease) and adult-onset diseases (coronary artery disease, diabetes).

Cleft Lip and Cleft Palate

Common craniofacial malformations due to disturbances during craniofacial structure fusion, which may require surgical and dental interventions.

Chromosomal Disorders

Major cause of miscarriages, congenital malformations, and intellectual disability. Involve abnormalities in chromosome number or structure.

Structural Chromosomal Abnormalities

Result from chromosome breakage and rearrangement, including deletions, inversions, isochromosome formation, ring formation, and translocations.

Chromosomal Disorders Involving Autosomes

Aneuploidy (abnormal chromosome number) results from nondisjunction. Monosomy (one chromosome) is severe. Polysomy (more than two chromosomes) includes trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), and trisomy 13 (Patau syndrome).

Down Syndrome

Most common chromosomal disorder (trisomy 21) combines intellectual disability, characteristic facial features, and other health issues. Risk increases with maternal age.

Chromosomal Disorders Involving Sex Chromosomes

More common than autosomal disorders. Imbalances are better tolerated due to X chromosome inactivation and few genes on the Y chromosome.

Turner Syndrome

Absence of all or part of the X chromosome (45, X/0), causing short stature and loss of oocytes. Management includes growth hormone and estrogen therapy.

Klinefelter Syndrome

Testicular dysgenesis with one or more extra X chromosomes (47, XXY), causing enlarged breasts, sparse hair, and small testes. Androgen therapy may be used.

Mitochondrial Gene Disorders

Mitochondrial DNA (mtDNA) disorders are maternally inherited and affect tissues dependent on oxidative phosphorylation, like the neuromuscular system. Clinical expression depends on the proportion of mutant mtDNA.

Disorders Due to Environmental Influences

Embryonic development is influenced by environmental factors, especially during organogenesis (days 15-60 post-conception).

Teratogenic Agents

Chemical, physical, or biological agents cause abnormalities during development. They include radiation, drugs, chemicals, and infectious agents.

Fetal Alcohol Syndrome

Physical, behavioral, and cognitive abnormalities due to alcohol consumption during pregnancy. No safe amount of alcohol is known.

Diagnosis and Counseling

The birth of a child with congenital defect can be assessed through genetic counseling to determine inheritance and recurrence risks. Prenatal diagnosis helps in detecting abnormalities.

Prenatal Screening and Diagnosis

Methods include ultrasonography, maternal serum markers, amniocentesis, chorionic villus sampling, and percutaneous umbilical fetal blood sampling.

Maternal Serum Markers

Blood tests to screen for fetal anomalies, including PAPP-A, AFP, hCG, inhibin A, and unconjugated estriol.

Amniocentesis

Withdrawal of amniotic fluid for analysis of fetal cells.

Chorionic Villus Sampling

Obtains tissue for fetal chromosome studies, DNA analysis, and biochemical studies.

Percutaneous Umbilical Cord Blood Sampling

Used for prenatal diagnosis of hemoglobinopathies, coagulation disorders, metabolic and cytogenetic disorders, and immunodeficiencies.