Congenital malformations congenital anomalies and birth defects Structural

Congenital malformations, congenital anomalies, and birth defects • Structural disorders that are present at birth, but also might appear sometime after birth • Teratology the science that studies the causes of anomalies • Teratogen: is an agent that causes abnormality. • Anomalies occur in 2 -3% of live born, in addition, another 2 -3% are recognized by age of 5 years. • 40 -60% of birth defects the causes are unknown. 15% are caused by genetic and chromosomal defects. 10% are caused by environmental factors, and 20 -25% are caused by combination of genetic and environmental factors.

Some Terms • Malformations: occur during formation of the structure • Disruption: result in morphological alterations of structure after their formation, due to destructive processes as vascular accidents • Deformation: are due to mechanical forces • Syndrome: refers to a group of anomalies occurring together, and usually have a common etiology. Association, refers to nonrandom appearance of two or more anomalies that frequently occur together.

Environmental Factors: Infectious Agents • Rubella or German Measles: Affecting : • The eye--- cataract, microphthalmia • Internal ear---congenital deafness • Heart--- persistence ductus arteriosus • Brain malformations • Intra uterine growth retardation • Dental defects

Cytomegalovirus • Microcephaly • Cerebral calcification • Blindness • Chorioretinitis • Hepatosplenomegaly

• Herpes Simplex virus: Microcephaly, microphthalmia, retinal dysplasia, Hepatosplenomegaly and mental retardation Infection during child birth-- • Varcella (chickenpox): limb hypoplasia, eye defects and CNS defect • HIV- Microcephaly, growth retardation, and face abnormalities • Other virus infections---abortion, fetal death Hyperthermia: abortion, neural defects, ….

• Toxoplasmosis: infection with toxoplasma gondii, a protozoan parasite, causes: Chorioretinitis, , cerebral calcification , microcephaly, hydrocephaly, visual impairment, hearing loss, and abortion. • Syphilis: congenital deafness, mental retardation, and diffuse fibrosis of the liver.

Physical Causes: Radiation • Ionizing radiation, X-ray: (1) kill proliferating cells (2) Mutation. Microcephaly, skull defects, spina bifida, blindness, cleft palate, and defects of extremities. • Low radiation: depleted uranium?

Chemical Agents • Drugs • Environmental chemicals. • Drugs: • Thalidomide: Amelia, and meromelia (total or partial absence of the extremities), heart defects and orofacial cleft. • Amniopterin, this is an antagonist of folic acid: anencephaly, meningocele, hydrocephalus, and cleft palate. • Phenytoin (diphenylhydantoin), valproic acid, and trimethadone— anticonvulsant drugs: craniofacial defects, digital and nails hypoplasia, growth abnormalities, mental retardation, and tube defects. • Valproic acid: Atrial septal defects, hypospadia, cleft palate, craniosynstosis, polydactyly • Carbamazepine; neural tube defects

• Antipsychotic drugs, such as phenothiazine and lithium……. ? Heart defect • Mepromate, chlordiazepoxide and diazepam(valium): cleft lip and cleft palate. • Antidepressant drugs: abortion, heart defects • Mycophenolate mofetil (immunosupressant): abortion, cleft palate, microcephaly, and heart defects.

• Warfarin ( anticoagulant drug), : hypoplasia of nasal cartilage, chondroplasia, and central nervous system defects, and optic nerve atrophy. • Angiotensin-converting enzyme inhibitors (antihypertensive drugs): growth retardation, renal dysfunction and fetal death.

Propylthiouracil and pottasium iodide: goiter and intellectual disability Streptomycin: deafness Sulfonamide: kernicterus Tetracyclin: bone and teeth abnormalities. Impramine: limb deformities Amphitamines: oral cleft, and cardiovascular defects Quinine: deafness LSD, phenucline, marijuana, , and cocaine: limbs and CNS abnormalities, and growth retardation. • Isotretinoin: flat nasal bridge, mandibular hypoplasia, cleft palate, neural tube defects and fetal death. • •

• Alcohol: (FASD=fetal alcohol spectrum disorders) • Fetal alcohol spectrum disorder: Intellectual disabilities, structural abnormalities of the brain, face and heart defects • Cigarette smoking: IUGR, orofacial defects

Hormones • Androgenic agents, such as synthetic progestins: masculinization of the genitalia in female • Diethylstilbesterol, (a synthetic estrogen): increases of the risk of development of carcinoma of vagina in females, and testis malformations in male • Environmental estrogens: male: testicular cancer, feminization of brain and hypospadia. In female: musculinzation of brain • Male-mediated Teratogens • Cortisone: cleft palate

Maternal Diseases • Diabetes: increase the risk of congenital defects like hear defects and sirenomelia • Phenylketonuria: intellectual disability, microcephaly and heart defects

Nutrition • • Iodine deficiency --- cretinism Folic acid deficiency Methyl-deficient diet Obesity: risk of heart defects and omphalocele • Excess of teratogens • Hypoxia

Environmental Chemicals • Lead : increase abortions, growth retardation, and neurological disorders. • Pesticides • Organic mercury • Heavy metals toxicity

Chromosomal and Genetic Factors • Numerical abnormalities: • The normal number is diploid or 2 n • Aneuploid refers to any chromosome number that is noneuploid, such as when there is an extra chromosome is present. • Trisomy: there is an extra chromosome, and the total number is 47: • Trisomy 21—Down syndrome: craniofacial abnormalities, upward slanting of the eyes, epicanthal folds, flattened face, cardiac defect, and mental retardation. • Trisomy 18: mental retardation, heart defects, low-set of ears, flexion of fingers and hand , micrognathia and renal anomalies

• Trisomy 13: mental retardation, holoprosencephaly, congenital heart defects, deafness, cleft lip and palate, and eye defects • Klinefelter syndrome: male, XXY— 47 chromosomes: sterility, testicular atrophy and gynecomastia. • Turner syndrome: female, XO, 45 chromosomes: absence of ovaries (gonadal dysgenesis), short stature, webbed neck and broad chest • Triple X syndrome: infantile and some degree of mental retardation.

Chromosomal structural abnormalities • Partial deletion , example: deletion of part of short arm of chromosome 5 ---cri-du-chat syndrome: microcephaly, mental retardation and congenital heart defects • Angleman syndrome: a deletion of part of long arm of chromosome 15: poor motor development, and mental retardation.

• Fragile X syndrome: mental retardation, large ears, prominent jaw and pale blue irides • Single gene mutation

Fetal Therapy • Fetal transfusion • Fetal medical treatment • Fetal surgery • Stem cells transplantation and Gene therapy