1、1CONGENITAL FETAL ANOMALIES 2TerminologyCongenital means exist since birth, whether clinical evidences are obvious or not obvious. Anomaly means a deviation from the normal. Malformation means faulty development of a structure 3Types of congenital anomalies: Physical structural defects: Single struc
2、ture is affected.Multiple structures are affected. Non-structural defectsInherited metabolic defectsFunctional and behavioral deficits e.g. congenital mental retardation.Incidence:Major congenital anomalies: affects about 2 to 5% of all newborns. Minor anomalies occur in higher percentage of newborn
3、 (about 10%). The risk of recurrence of congenital malformations with the same patient is very important in genetic counseling. Most of congenital anomalies are single primary developmental anomalygeneral empirical average figure of 2 to 5%, to the apparently known healthy parents with one affected
4、child. More accurate figures could be calculated only when the etiology is due to a defect in a single gene and according to the laws of inheritance e.g. hemophilia4Etiology of Congenital AnomaliesUnknown cause (60%): The causes of malformations are not identifiable in the majority of cases. Multifa
5、ctorial factors (20%):Multifactorial etiology denotes the presence of an interaction between genetic predisposition and non-genetic intrauterine factors. Common examples include neural tube defects, certain forms of hydrocephaly, facial clefts, cardiac anomalies, and imperforate anus. 5Genetic basis
6、: Thousands of known genetic diseases that may affect humans as all inherited disordersAre passed from one generation to another. Genetic diseases may be secondary to either of the following: Secondary to a single mutant genes (7.5%): Mendelian single gene disorders that carries a risk of causing co
7、ngenital malformations.Autosomal dominant and recessive disorders: About 3000 disorders are inherited in humans due to single gene disorder. e.g Hemoglobinopathies. sickle cell disease, thalassemia&Renal disorders: polycystic kidney disease.Sex chromosomal traits (X-linked diseases): There is no mal
8、e to male transmission e.g. hemophilia, muscular dystrophy. 6Secondary to chromosomal anomalies (6%). Abnormality of chromosome number (numerical abnormalities):Triplicate number of portion or an entire chromosome: clinically - Autosomal abnormalities: e.g. Trisomies e.g. trisomy 21, 18 and 13. Tris
9、omy 13 and 18 are fatal.- Sex chromosome anomalies: The most common are Turners syndrome (45,X), Kleinfelters syndrome (47,XXY).Monosomies: Single number of chromosome: monosomy X. e.g. X-linked mental retardation (fragile X syndrome). Abnormality of chromosome structure: Deletions, translocations,
10、inversions.7Exogenous influences Teratogen exposures :Teratogenesis mostly occurs before the tenth week of intrauterine life (the period of embryogenesis). Intrinsic insults:Maternal infections: rubella virus, cytomegalovirus, toxoplasmosa gondi, human parovirus B19 infection, and syphilis. Noninfec
11、tious systemic e.g. diabetes mellitus, phenylketonuria, and seizure disorders.Functional virilizing lesions of the ovary and adrenal glands.Extrinsic insults: Environmental agents: organic solvents, pesticides, anesthetic gases and heavy metals like lead, lithium, and organic mercury.Drug exposure a
12、nd medications: Examples of known human teratogenic medications: Hormonal agents: Progesterone , androgenic hormones causing masculinization of the female fetus and thyroid and antithyroid drugs. Thalidomide causing phocomelia and other limb congenital malformations. Physical injury: Exposure to hig
13、h doses of ionizing radiation produces gene mutation, chromosomal aberrations and abnormalities. 8The Food and Drug Administration “FDA” lists five categories of tabling for drug use in pregnancy A.Controlled studies in women failed to demonstrate a risk to the fetus in the first trimester, and the
14、possibility of fetal harm appears remote.B.Animal studies do not indicate a risk to the fetus, there are no controlled human studies, or animal studies do show an adverse effect on the fetus, but well controlled studies in pregnant women have failed to demonstrate a risk to the fetus.C.Studies have
15、shown the drug to have animal teratogenecity or embryocidal affects, but no controlled studies are available in either animals or women.D.Positive evidence of human fetal risk exists, but benefits in certain situations (e.g., serious diseases for which safer drugs are ineffective) may make use of th
16、e drug acceptable despite its risks.X.Studies in animals or humans have demonstrated fetal anomalies and the risk clearly outweighs any possible benefit.910Prevention Of Having An OffspringWith Congenital AnomaliesPre-Pregnancy assessmentAntenatal DiagnosisPostnatalAssessmentGeneral Guidelines11I. G
17、eneral guidelines:Control of medications during pregnancy: Minimize drug exposure.Detection and control of relevant maternal diseases.Genetic counseling.Prenatal diagnosis of genetic conditions and selective termination of the affected pregnancy or in-utero treatment if possible.Discourage consangui
18、neous marriages when appropriate e.g. closed family, previous inheritable malformation in the family. 12Pre-Pregnancy AssessmentGenetic counseling: A pre-pregnancy information given to couples with family history of congenital and inherited disorders, helping them to make a decision regarding future
19、 childbearing. The correct advice provides accurate information concerning the recurrence risks. General screening programs: The aim is to identify some of the common genetic disorders in a community. Adult screening programs in selected high-risk groups:Common examples of autosomal recessive disord
20、ers: sickle cell anemia, thalassemia major.Gravidas over 35 years: Cytogenic studies on fetal cells obtained by amniocentesis or chorionic villus sampling. Neonatal screening programs: Some of the disorders that are in needs for immediate identification after delivery and to be screened soon after d
21、elivery are phenylketonuria, congenital hypothyroidism, sickle cell disease and galactosemia. 13Pre-natal Diagnostic ProceduresHistory TakingAbnormal findings during routine examinationAbnormal findings during routine investigationsSpecific Antenatal diagnostic procedures 14History Takingleading que
22、stions of special significance: Maternal age. Personal or family history of congenital anomalies e.g. familial disorders in the blood relatives. The ethnic origin. Significant maternal diseases: diabetes mellitus, infections, and acute maternal illness. 15Suspicious Findings On Clinical ExaminationA
23、 higher incidence of congenital anomalies are detected in association with :Oligohydramnious: renal dysplasia, renal agenesis, bladder outlet obstruction and intrauterine growth retardation.Polyhydramnios: Central nervous system anomalies: anencephaly, hydrocephaly.Gastrointestinal malformations: Tr
24、acheoesophageal fistula, duodenal atresia.Threatened abortion. Unexplained IUGR.16Suspicious Findings On Routine InvestigationsSuspicious findings on ultrasound screening:Early IUGRIUGROligohydramniosHydramniosRestricted fetal movements 17Abnormal maternal serum alpha-fetoprotein (MSAFP) MSAFP is el
25、evated (2.5 MOM) Fetal anomalies such as neural tube defects, abdominal wall defects e.g. omphalocele, esophageal or intestinal obstruction, cystic hygroma, urinary obstruction, renal anomalies: polycystic kidneys, osteogenesis imperfecta, Turners syndrome, and Rh disease.Obstetrical complications s
26、uch as low birth weight, oligohydramnios, multifetal gestation.MSAFP is abnormally low ( 5 mm.Placental thickening: 4 cm.Body cavities: Significant pleural and pericardial effusions and ascites. 65Hydrops FetalisCauses of fetal hydrops: Immune hydrops fetalis. Due to chronic intrauterine anemia. The
27、 well-known example is Rh isoimmunization. Non-immune hydrops fetalis: Generally it has a high incidence of mortality.Fetal cardiac arrhythmias e.g. supraventricular tachycardia. Due to heart failure.Fetal structural cardiac anomalies e.g. hypoplastic left heart, due to heart failure.Pulmonary hypop
28、lasiaRenal dysplasia.HypoproteinaemiaCongenital nephrosis. Intrauterine infections: due to chronic intrauterine anemia e.g. toxoplasmosis, rubella, cytomegalovirus infections, congenital hepatitis, parvovirus infection. Chromosomal abnormalities: e.g. Turners syndrome, trisomy 18 or 21. Congenital h
29、ematological disorders: e.g. thalaaemia.Twin-to-twin transfusion.66Downs syndromeIt is Trisomy 21 syndrome. Incidence: general incidence is 1:600. The incidence rises with increase of maternal age. 1:365 at 36 years and 1:40 at the age of 40 yearsNeonatal features:Head: Flat face and flat occiput, t
30、hird fontanelle, upward slanted palpebral fissure, inner epicanthal folds and simply formed ears, nose: small, flat nasal bridge, mouth: small and the tongue protrudes.Neck: short, broad. Loose folds in posterior neck.Hands: simian single palmar crease, short metacarpals and phalanges. Hypotonia. Sh
31、ort humerus and femur Heart: High incidence of cardiac defects e.g. artrioventricular canal defect.Increased incidence of leukemiasGastrointestinal: Duodenal atresia, Hirschsprungs disease. 67Antenatal DiagnosisFirst trimester Increased Nuchal ThicknessPAPP-AFailure to detect the nasal bone68When th
32、e nasal bone line appears as a thin line, less echogenic than the overlying skin, it suggests that the nasal bone is not yet ossified, and it is therefore classified as being absent 11-13+6 weeks69Second Trimester ScreeningThe Triple TestThe Quad TestTriple Test + Dimeric Inhibin A (DIA)Integrated first and Second Trimester ScreeningDiagnostic procedures MUST involve genetic testing of samples obtained from the baby70
