Congenital+Anomalies+and+Teratogenesis

=**Objectives**=


 * 1. Review the causes of congenital anomalies.** (p.581)

Congenital anomalies can be caused by chromosomal abnormalities, Mendelian and atypical inheritance disorders, multifactorial abnormalitlies, environmental/teratogeneic anomalies,and unknown causes.


 * 2. Review the incidence and clinical significance of congenital anomalies.** (p.580-582)

50% of congenital anomalies are of unknown cause.


 * Category**||**Types**||**Incidence**||
 * Chromosomal||Aneuploidy, UPD, Microdeletion||6%||
 * Mendelian (Single Gene), Atypical Inheritance||AD, AR, XLD, XLR, Y-linked, Imprinting, triplet repeat, expansion disorders, mitochondrial||7.5%||
 * Multifactorial||Common birth defects||20-30%||
 * Environmental (Teratogenic)||chemical, physical, and infectious agents||5-10%||


 * 3. Compare and contrast the concepts of malformation, deformation, disruption, sequence, syndrome, and association.** (p.583, 589, 593, 596, 599, 600)

__Malformation__ Primary structural defect resulting form error in tissue formation. These can arise from incomplete, redundant, or aberrant morphogenesis. Incomplete morphogenesis is the most common malformation and refers to the lack of development, incomplete development (hypoplasia), incomplete closure (myelomeningocele, occipital encephalocele, anencephaly), incomplete separation (sirenomelia), and persistence of early location. Redundant morphogenesis is uncommon (polydactyly, etc.) while aberrant morphogenesis is rare (mediastinal thryproid gland -- thyroid gland development in the wrong place). Congenital malformations that are initiated later are more easly to correct; earlier maifestations during organogenesis tend to have more severe consequences.

Malformations typically occur at the embryonic stage and result in organ disturbance and high perinatal mortality. They have a high recurrance rate because they often have genetic causes.

__Deformation__ Alternation in shape of position of a normally developed structure. These can arrise from mechanical, malformational, and functional disturbances. Mechanical disruptions can occur due to uterine constraint, amniotic tear with chronic leakage, oligohydramnios, unusual fetal position, twin fetuses, malformed fetus, large fetus/large head. Malformational deformations can be due to genetic errors resulting in spina bifida and other CNS malformations, and bilateral renal agenesis. Functional disructions can be caused by neurological/muscular disturbances (i.e., babies that don't move around in utero can have underdeveloped muscles).

Deformations typically occure at the fetal stage and result in regional disturbances. Perinatal mortality is low with high spontaneous correction, correction by posture, and correction by surgery rates. Relative recurrance rate is lower than malformations.

__Disruption__ Destruction of previously normally developed structure.

Disruptions can occur during the embryonic and fetal stages and and result in area disturbance. Perinatal mortality is high with extreme variability in clincal preesentation of any given anomaly. Relative recurrance rate is extremely low.

__Sequence__ Multiple anomalies which result from a single primary anomaly or mechanical factor. That is, intrinsic and extrinsic causes resultin a primary anomaly which in turn causes several secondary anomalies.

__Syndrome__ A series of multiple, non-sequential pathogenetically related anomalies

__Association__ A non-random occurence of multiple anomalies not yet known to represent a developmental field defect, syndrome, or sequence.


 * 4. Provide clinical examples of a malformation, deformation, disruption, sequence, syndrome, and association that illustrate the pathogenetic mechanism of each.** (p.584, 589, 593, 596, 600)

__Malformation__ Incomplete Morphogenesis: Renal agensis, macrognathia (small lower jaw), cleft palate, ventricular septal defect, low-set ears, undescended testes Redundant Morphogenesis: Supernumerary ear tag, polydactyly Aberrant Morphogenesis: Medistinal thyroid gland

__Deformation__ Mechanical: Craniosynostosis, constraint-related growth deficiency, deformation following prolonged delivery.

__Disruption__ Amniotic banding: Amniotic sac rupture can lead to fluid loss and detachment of amniotic sac. The amniotic membrane can get entwined and cut off vasculature of developing limb, resulting in limb reduction. Severity of reduction depends on the location of vascular occlusion.

__Sequence__ Potter sequence: Amniotic rupture (disruption) or renal agenesis (malformation) results in reduced amniotic fluid in the amniotic sac causing oligohydromnios and fetal constraint (primary mechanical factors). Theis results in several secondary anomalies: potter faces, fetal growth deficiency, pulmonary hypoplasia, breech positon, limb position defects.

__Syndrome__ DiGeorge Syndrome/Velocardiofacial Syndrome: Developmental field defect caused by a chromosome 22q11.2 deletion. This defect results in defects in the development of a series of structures including knocking out the development of the thymus (resulting in immunodeficiency) and the parathyroid (resulting in calcium regulation problems and lack of PTH) and causing heart defects.

__Association__ CHARGE Association - Coloboma, heart defect, atresia choanae, retarded growth, genital anomalies, ear anomalies/deafness VATER Association - Vertebral anomalies, anal atresia, tracheoesophageal fistula, radial and renal anomalies


 * 5. Review the three types of abnormal morphogenesis and provide an example of each.** (p.583)

Incomplete Morphogenesis: Renal agensis, macrognathia (small lower jaw), cleft palate, ventricular septal defect, low-set ears, undescended testes Redundant Morphogenesis: Supernumerary ear tag, polydactyly Aberrant Morphogenesis: Medistinal thyroid gland


 * 6. Review the concept of teratogenesis with regard to causes, mechanisms, and manifestations.** (p.602)

Teranogenesis refers to the action by an agent from the environment on germ cells, embryos, or fetuses producing reactions within germ cells, embryoes or fetuses leading to pathogenesis.


 * 7. Acquire an appreication for the temporal sensitivity of the fetus to teratogeneic agents.** (p.601)

Most organ development has a heightened temporal sensitivity to teratogenic agents during embryonic development. Major malformations can occur from exposure during the first 3-8 weeks of development while more functional defects and minor malformations can occur from exposure from 9-28 weeks of development.


 * 8. Review common syndromes caused by teratogeneic agents including fetal alcohol syndrome, maternal diabetes, thalidomide embryopathy, and retinoic acid embryopathy.** (p.602-603)

__Fetal Alcohol Syndrome__ Ethanol exposure can cause fetal alcohol syndrome, manifest by low birth weight, growth delay and heart defects. Also charactersitic are short palpebral fissures, shrot noise, long philtrum, and thin upper lip.

__Maternal Diabetes__ Infantsof diabetic mothers who do not control their blood sugar levels can manifest large birth weight (macrosomia), brain anomalies, and heart defects.

__Thalidomide Embryopathy__ Thalidomide's anit-angiogenesis effects can result in infants with phocomelia and heart and ear anomalies.

__Retinoic Acid Embryopathy__ High retinoic acid exposure during pregnancy can result in craniofacial defects (downwardslanding palpebral fisues,micrognathia, displaced hair whorl), heart and limb defects, and severe developmental disorders (fluid in brain resulting in expanded ventricles)


 * 9. Review common drugs and infectious agents with a teratogenic effect.** (p.603, 606)

__Common Drugs with Teratogenic Effects__


 * Drug**||**Effect**||
 * Alcohol||Heart defetcs, microencephaly, characteristic faces||
 * Diethylstilboestrol (DES)||Uterine malformations, vaginal carcinoma||
 * Lithium||Heart defects (Ebstein's anomaly)||
 * Phenytoin (Dilantin)||Heart defects, cleft palate||
 * Streptomycin||Deafness||
 * Tetracycline||Dental enamel hypolasia||
 * Thalidomide||Phocomelia, heart and ear anomalies||

__Infectious Teratogenic Agents__


 * Virus**||**Effect**||
 * Cytomegalovirus||Deafness, microcephaly, chorioretinitis||
 * Herpes Simplex||Microcephaly, microphthalmia||
 * Rubella||Microcephaly, cataracts, heart defects||
 * Varicella zoster||Microcephaly, chorioretinitis||


 * Bacteria**||**Effect**||
 * Syphilis||Hydrocephalus, osteitis, rhinitis||


 * Parasites**||**Effect**||
 * Toxoplasmosis||Hydrocephalus, microcephaly, cataracts, deafness||