1. Dysplasia
1.1. ABNORMAL ORGANIZATION OF CELLS INTO TISSUES
1.2. EX: achondroplasia
1.2.1. fibroblast growth receptor 3 single gene defect affects the progression of cartilage to bone & results in the typical phenotype
1.2.2. short stature w/ short arms & legs, normal torso
1.2.3. high forehead, low nasal bridge
1.2.4. normal cognition
2. Causes of congent. anomalies
2.1. unknown etiology (most common)
2.2. Multifactoral inheritance (2nd most common)
2.2.1. Often a single major defect
2.2.2. EX: spina bifida
2.2.2.1. recurrence rate > random
2.2.2.2. some modifiable risk factors (folic acid, seizure meds
2.2.2.3. exact cause not known
2.2.3. other ex: cleft lip/palate, developmental dysplasia of the hip
2.3. Environmental agents
2.4. Mutant genes
2.5. chromosomal abnorm. (least common)
2.5.1. ANEUPLOIDY=EXTRA OR MISSING CHROMOSOME
2.5.1.1. cause: nondisjunction during meiosis: both members of chromosome pair stay together rather than one going to each daughter cell
2.5.1.2. 1 new cell has 22 chromosomes & one has 24
2.5.1.3. risk INCREASES W/ MATERNAL AGE
2.5.1.4. Missing chromosome usually not compatible w/ life
2.5.1.5. Aneuploidy-Trisomy 21 "Down Syndrome"
2.5.1.5.1. most common autosomal trisomy
2.5.1.5.2. 1/600-1/800
2.5.1.5.3. Features:
2.5.1.5.4. Diagnosis:
2.5.1.6. Trisomy 18"Edwards Syndrome"
2.5.1.6.1. much less common; 1/8000
2.5.1.6.2. Features:
2.5.1.6.3. shortened life span
2.5.1.7. Trisomy 13"Patau Syndrome"
2.5.1.7.1. 1/12,000
2.5.1.7.2. Features
2.5.1.7.3. Very short life span
2.5.1.8. 45XO"Turner Syndrome"
2.5.1.8.1. only 1% fetuses w/ this chromosome complement survive to delivery
2.5.1.8.2. 1/8000 births
2.5.1.8.3. Features:
2.5.2. Translocations
2.5.2.1. 4%of cases (important to know b/c changes recurrence risk
2.5.3. Polyploidy=extra set of chromosomes
2.5.3.1. triploidy most common (69 chromosomes)-fetal death
2.5.3.2. often caused when egg is fertilized by more than 1 sperm
2.5.4. Deletions: chromosome breakage results in LOST SEGMENT & therefore a contiguous portion of genetic information
2.5.4.1. Ex: CRI DU CHAT syndrome (deletion of critical segment of short arm of chrom. 5)
2.5.4.1.1. high pitched cry in infancy
2.5.4.1.2. dysmorphic features
2.5.4.1.3. severe cognitive impairment
2.5.4.1.4. congenital heart dx
2.5.5. Point mutations
2.5.5.1. change in single gene results in disease process
2.5.5.1.1. Ex: ACHONDROPLASIA (autosomal dominant)
2.5.6. TRIPLET REPEAT EXPANSION
2.5.6.1. from one generation to the next, a gene segment of 3 nucleotide repeats expands, eventually causing symptoms/physical findings
2.5.6.2. Increasing # of diseases found to be caused by these types of mutations
2.5.6.2.1. tend to affect CNS (HUNTINGTONS, SPINOCEREBELLAR ATAXIAS)
2.5.6.3. ANTICIPATION:decreased age of onset & increased severity w/ successive generations (felt to be due to enlarging region)
2.5.6.4. EX: FRAGILE X SYNDROME (most common heritable cause of intellectual disability) approx. 1/4000
2.5.6.4.1. Frag X typical findings
2.5.6.5. FMR1 gene on x chromosome usually has 5-44 CGG repeats
2.5.6.5.1. 55-199 is a premutation
2.5.6.5.2. > or = is diagnostic
2.5.6.6. Penetrance
2.5.6.6.1. 100%in males (only 1 x chromosome)
2.5.6.6.2. 50%females (who also have a normal x chromosome)
3. Maternal infections
3.1. TORCH
3.1.1. Toxoplasma
3.1.2. Syphilis (other)
3.1.3. Rubella
3.1.3.1. Multiple anomalies, most common = HEARING IMPAIRMENT, CONGENITAL HEART DX & CONGENITAL CATARACTS,also intellect disability
3.1.3.2. highest risk=first 10wks of preg
3.1.3.3. spreads trans-placentally &thru fetal circulation, damaging the developing vasculature
3.1.3.4. Risk to fetus is 80-85% for infection in the 1st trimester, much lower after 18wks gestation
3.1.3.5. vaccine preventable(occasion. cases in US due to immigration of unimmunized mothers
3.1.4. CMV (MOST COMMON TORCH)
3.1.5. Herpes
3.2. Zika
3.2.1. microcephaly
3.2.2. knowledge is evolving rapidly
3.2.3. infection w/ this virus during pregnancy can cause
3.2.3.1. severe microceph.
3.2.3.2. structural brain abnorm
3.2.3.3. eye abnorm
3.2.3.4. joint contracture
3.2.3.5. LONG TERM RISKS ARE NOT KNOWN
4. Tobacco
4.1. nicotine causes vasoconstriciton
4.1.1. association w/ nicotine & limb reduction defects, gastroschisis, cleft lip
4.1.2. Affects placental function: fetus doesn't grow well = intrauterine growth restricition
4.2. MANY other chemicals present in cigarette smoke: who knows what they all do or if they are safe?
5. Teratology
5.1. study of classification of anomalies & understanding the developmental anatomy
5.2. principles:
5.2.1. critical periods of development
5.2.1.1. certain exposures may cause harm @ particular points ¬ @ others
5.2.2. Dose response
5.2.3. Genetic vulnerability of the fetus
6. Malformation
6.1. abnormality is intrinsic to the tissue;THERE WAS NEVER POTENTIAL FOR NORMAL DEVELOPMENT
6.2. cause can be genetic, environmental
6.3. ex: phocomelia-limb deficiency
6.4. this term gets thrown around a lot
7. Deformation
7.1. an inherently NORMAL STRUCTURE IS PERMANENTLY ALTERED BY MECHANICAL FORCES
7.2. EX:talipes equinovarus
7.2.1. normal foot that has molded into abnormal positions, the tx is to mold back to neutral
8. Disruption
8.1. NORMALLY DEVELOPING TISSUE IS ALTERED/DAMAGED BY EXPOSURE OR EVENT
8.2. EX:amniotic band
8.2.1. normal tissues are constricted or even amputated by bands of amniotic tissue
8.3. EX: gastroschisis
8.3.1. vascular event causes abd. wall defect
8.3.2. viscera outside body; are not covered by any membrane
8.3.3. usually an isolated finding
8.3.4. occurs in 3-4/10,000 preg
9. Incidence
9.1. major congenital anomalies
9.1.1. significant health consequneces
9.1.2. EX: spina bifida, congenital heart dx
9.1.3. 3-4% NEWBORNS HAVE A MAJOR ANOMALY
9.1.4. account for 20% of perinatal deaths
9.2. minor congen.anomalies
9.2.1. not individually significant
9.2.2. EX: accessory nipple, preauricular tag
9.2.3. more common, 14% of infants
9.3. Of infants w/ 3 or > minor anomalies 90% also have a major anomaly
10. Teratogens:exposures known to cause fetal anomalies
10.1. Meds:
10.1.1. Thalidomide: limb foreshortening, taken off market
10.1.2. Isotretinoin (Accutane)
10.1.2.1. Craniofacial, cardiac & CNS abnormalities
10.1.2.2. 20-30% preg loss, 20-30% liveborn infants are affected
10.1.2.3. iPledge program
10.1.3. Antiepileptic meds
11. Alcohol
11.1. no safe dose
11.2. Fetal alcohol spectrum disorder: different degree & timing of exposure results in different outcome
11.3. Physical changes:
11.3.1. long smooth filtrum
11.3.2. thin upper lip
11.3.3. short nose
11.3.4. anteverted nares
11.4. Neurobehavioral differences
12. Dysmorphology
12.1. EVALUATING PATTERNS OF MALFORMATION TO TRY TO IDENTIFY A CAUSE OR UNIFYING DIAGNOSIS
12.2. isolated
12.3. syndrome
12.3.1. SET OF FINDINGS THAT ARE SEEN TOGETHER W/ SHARED ETIOLOGY
12.3.2. EX:Treacher Collins syndrome
12.3.2.1. autosomal dominant mutation TCOF1 gene w/ variable penetrance
12.3.2.2. Malar hypoplasia
12.3.2.3. cleft zygoma
12.3.2.4. eye anomalies (coloboma, absent lashes)
12.3.2.5. ear anomalies
12.3.2.6. hearing loss
12.3.2.7. NO intellectual disability
12.4. sequence
12.4.1. A SINGLE ABNORMALITY IN DEVELOPMENT LEADS TO A CASCADE OF PREDICTABLE ASSOCIATED FINDINGS
12.4.1.1. EX: Pierre Robin sequence
12.4.1.1.1. lower jaw fails to develop normally in 9th wk of gestation
12.4.1.1.2. tongue remains interposed b/w palatal shelves-->cleft palate
12.4.1.1.3. retrognathia leads to glossoptiosis
12.5. association
12.5.1. GROUP OF ANOMALIES THAT ARE SEEN TOGETHER MORE OFTEN THAN WOULD BE EXPECTED BY CHANCE BUT DO NOT SHARE A COMMON CAUSE
12.5.2. EX: CHARGE association
12.5.2.1. Coloboma
12.5.2.2. Heart Dx
12.5.2.3. Choanal Atresia
12.5.2.4. growth Retardation (and/or intellect disabil.
12.5.2.5. Genital anomalies
12.5.2.6. Ear anomalies
12.5.3. the cause is not known
12.5.4. additional EX: VATER/VACTERL association
12.5.4.1. Vertebral anomalies
12.5.4.2. imperforate Anus
12.5.4.3. Cardiac anomalies
12.5.4.4. TE fistula
12.5.4.4.1. HALF OF BABIES W/ TEF HAVE ANOTHER CONGEN. ANOMALY
12.5.4.5. Renal anomalies
12.5.4.6. Limb anomalies
12.5.4.7. occurence sporadic 1/10,000-1/40,000