Congenital anomalies that you should know

Childhood abnormalities

For children below 12 years old, the most leading causes of death are congenital anomalies. However, beyond this age other leading causes include accident and adverse effects, malignant cancers, lower respiratory tract infections. Our focus shall be on congenital anomalies, perinatal infections and childhood tumors.

Congenital anomalies

Congenital anomalies are structural defects present in a live born infant. When the anomaly is less severe, fetal development may continue to live birth or end in still birth. Contrarily, very severe defects affect embryogenesis and lead to spontaneous abortion. Importantly, not all congenital defects result directly from gene mutations. They may as well arise from environmental causes.

Important terminologies used in errors of morphogenesis

Malformation: This is a primary abnormality arising from an internal error in the fetal developmental process. It may be caused by interaction between genetic and environmental factors. Examples include: polydactyly, syndactyly, cleft lip and palate, holoprosencephaly. 

Disruption: Secondary damage to a previously normal organ arising from external causes of disturbance in fetal development. The amniotic band from amniotic sac rupture, and various environmental agents cause disruptions.

Deformation: Compression of a growing fetus arising from biomechanical factors. These factors include: first pregnancy; small uterus; uterine fibroid; bicornuate uterus; uterine constraint accompanying growing fetus; oligohydramnios; abnormal fetal presentation.   

Syndrome: A group of congenital anomalies that are pathologically related and cannot by explained by just a single cause.

Sequence: Group of congenital anomalies caused by one initiating agent. E.g. oligohydramnios sequence initiates fetal compression against uterine wall resulting in clubfoot, flat face, pulmonary hypoplasia, hip dislocation. The causes of oligohydramnios may include: maternal hypertension (causes uteroplacental insufficiency); fetal renal agenesis; chronic amniotic fluid leakage (from infection).  

Organ-specific terms

Agenesis: Total absence of an organ along with its cell of origin (primordium).

Aplasia: Absence of an organ arising from the failure of the primordium to develop.

Atresia: Absence of the opening of a visceral organ e.g. esophagus, intestine.

Hypoplasia: Incomplete organ development resulting from a decrease in the numbers of cells and cell size.

Hyperplasia: An increase in the numbers of cells resulting in large organ size or mass.  

Dysplasia: An abnormal organization of cells within a tissue or organ.

Next, we shall discuss the causes of congenital diseases. The causes can be divided into genetic, environmental and multifactorial causes.

Chromosomal abnormality and single gene mutation

Aneuploidy and other chromosomal abnormalities result in congenital anomalies such as: Down syndrome; Patau syndrome; Edward syndrome; Turner syndrome; Angelman syndrome; Prader-Willi syndrome.

Single gene mutations result in anomalies such as: holoprosencephaly; congenital adrenal hyperplasia; Nieman-Pick disease; Bruton’s agammaglobulinemia, achondroplasia.

Viral infections

Viruses such as rubella, cytomegalovirus, herpes simplex, HIV can infect the mother and cause fetal malformation. In some cases, the gestational age at which infection occurs is critically important. Fetal defects decrease if infection occurs later during gestation. Cytomegalic inclusion disease, congenital rubella syndrome are common congenital diseases.

Most prominent clinical features of Cytomegalic inclusion disease include mental retardation; deafness; hepatosplenomegaly, and microcephaly.

In congenital rubella syndrome clinical signs include: deafness, mental retardation, cataracts; pulmonary artery hypoplasia or stenosis; persistent ductus arteriosus; tetralogy of Fallot; ventricular septal defect.

Drugs and other chemicals

Several drugs and other chemicals have shown to be teratogenic, therefore avoidance during pregnancy should be advised. They include: folate antagonists, thalidomide, androgenic hormones, 13-cis-retinoic acid, warfarin, anticonvulsants. 

Thalidomide, an immunomodulatory, antineoplastic, anti-angiogenic drug has a high teratogenic effect during pregnancy and may cause limb abnormalities.

Alcohol taken during pregnancy may result in fetal alcohol spectrum disorders (FASDs) and fetal alcohol syndrome.

Fetal alcohol spectrum disorders are structural anomalies, cognitive and behavioral defects that arise from alcohol use in pregnancy.

Structural anomalies in fetal alcohol syndrome include; growth retardation, microcephaly, maxillary hypoplasia, short palpebral fissures.

Nicotine in cigarette smoke has a high risk of causing spontaneous abortion, premature labor, placental abnormality, low birth weight. and sudden infant death syndrome.  

Radiation

This has a teratogenic effect on fetal development. Defects due to radiation include: microcephaly; blindness; spinal bifida; skull abnormalities and other deformities.

Maternal diabetes

When there is no regulation of maternal blood sugar level, this will result is fetal hyperinsulinemia. Fetal hyperinsulinemia causes: body fat and muscle mass increase, fetal macrosomia (organomegaly); cardiac defects; neural tube defects, CNS abnormalities. 

Multifactorial causes

An interaction between environmental factors and inherited susceptible genes plays a significant role in causing fetal malformation. E.g. the use of folic acid in preventing neural tube defects; frank breech position of a fetus with a weak abnormal hip joint in congenital dislocation of the hip.

The mechanism of congenital anomaly

Two important principles underlie the pathogenesis of fetal malformation. The prenatal age injurious agent is initiated and multifactorial Pathologic mechanism.

The prenatal age injurious agent is initiated can be accounted for by stages during organogenesis and fetal growth cell injury occurs. The first three weeks of gestation are critical during embryogenesis, at which point any severe injuries may cause cell death and abortion.

Between 3 to 9 weeks, organogenesis can be affected setting the foundation for malformation. Any injury occurring ≥9 weeks of gestation may affect fetal growth and development.

The multifactorial pathologic mechanism involves the effects of environmental factors on susceptible genes. Any exposure to environmental agents during pregnancy may affect signaling pathways regulated by certain sensitive gene components.

Excessive exposure to retinoic acid during pregnancy causes retinoic acid embryopathy. This includes CNS abnormalities, cardiac defects, cleft lip and palate. In this disease, retinoic acid deregulates special components involved in palatogenesis in the tumor growth factor-β (TGF-β) pathway.

Vitamin A deficiency during pregnancy also affects embryogenesis. Absence causes malformations in the eye, genitourinary system, diaphragm, lungs, heart, blood vessels.

An anti-convulsant, valproic acid taken during pregnancy causes valproic acid embryopathy. Intake of this medication inhibits the expression of homeobox (HOX) protein, a transcription factor encoded by homeobox gene. This transcription factor regulates gene expressions responsible for organogenesis involving limbs, vertebrae and craniofacial structures.

Infection during pregnancy

Infection to a fetus may occur early or later during fetal development and cause disruption. Two routes are possible which are transcervical and transplacental infection.

Transcervical infections happens in an ascending pathway from vagina to cervix and then to endometrium. It may also be transferred through chorionic villi to infect the fetus.

Inhalation of amniotic fluid by the fetus causes meningitis, sepsis and pneumonia. Chorioamnionitis may lead to premature labor due to release of prostaglandins. Most bacteria and few viruses such as herpes simples 2 infect through this route. Infection may also be transmitted during delivery.

Transplacental infections occur directly from placenta to the fetus through capillaries of the chorionic villi. Most viruses, parasites (malaria) and few bacteria are transmitted through this route. Infection may also be transmitted during delivery.

The transplacental infection causes TORCH syndrome: pneumonitis; chorioretinitis; fever; hemolytic anemia; encephalitis; hepatosplenomegaly; myocarditis; vesicular and hemorrhagic rashes; growth & mental retardation; cataract; bone & cardiac defects.

1. T: Toxoplasmosis
2. O: (Others: syphilis; parvovirus; zika virus; varicella zoster)
3. R: Rubella
4. C: Cytomegalovirus
5. H: Herpes simplex 

Early onset perinatal sepsis acquired shortly before birth presents symptoms within 7 days of child’s birth. Symptoms may include: pneumonia and bacterial meningitis. Group B streptococcus is usually the cause.

Late onset perinatal sepsis presents symptoms from 7 days to 3 months after child’s birth. Listeria and candida are usually isolated in microbiological specimens.