Developmental Anat. Block A

• new life arises from slime and decaying mater
• held from the time of Galen for nearly 1500 years

father of medicine

founder of embryology

theory that the fetus developed from a coagulation of blood and semen in the uterus (Jacob Rueff)

• sperm or ovum contain a germ that is completely formed but minute and invisible and expands to visible size and form during development
• theory of Homunculus

• egg lacks internal organization, some outside force causes development through use of cells
• theory holding the development is a gradual process of increasing complexity

• all animal embryos are composed of three primary germ layers (von Baer)
• ectoderm, mesoderm, and endoderm

the body is composed of cells and cell products (Schleiden and Schwann)

• ontogeny mimics phylogeny (Haeckel)
• claims that each embyro in its development passes through abbreviated stages that resemble developmental stages of its evolutionary ancestors

• the complete developmental history of an individual being
• describes the complete life period of an individual from fertilization to death

the complete developmental history of a species or group of animals

• artificial insemination
• in vitro fertilization
• transplantation

• CT scan
• ultrasound
• amniocentesis
• chorionic villis sampling

• to determine whether the baby's lungs are mature enough for an early delivery if you appear to be in premature labor or require an early delivery for any reason
• to diagnose or rule out a uterine infection
• most commonly done between 15-18 weeks
• to determine whether the baby has genetic or chromosomal abnormalities
• Rh sensitization, Down syndrome, other trisomies, spina bifida, anencephaly

• performed between 10-12 weeks under ultrasound observation
• analysis of cells from chorionic villus enables the detection of over 200 diseases and disorders
• performed transcervically or transabdominally

• surgical treatment of the fetus
• requires understanding of congenital abnormalities and normal development is required

an infant aged 1 month or less

• earliest period of extrauterine life
• ~ the first year after birth

• period from 13 months until puberty or sexual maturity
• period between infancy and puberty

is the period between the ages of 12 and 15 years in girls and 13 and 16 years in boys during which secondary sexual characteristics develop and the capability of sexual reproduction is attained

period from about 11 to 19 years of age, which is characterized by rapid physical and sexual maturation

• attainment of full growth and maturity
• generally reached between ages of 18 and 21 years

the developing individual from fertilization until the end of the 8th week

the developing individual in utero from the end of the 8th week until birth

the first diploid cell formed by the union of the sperm and ovum

the period of development prior to birth

abnormalities or malformations detected at birth or shortly thereafter

• marked deviation from the average or normal standard
• congenital defect
• may be structural or metabolic

• a morphological defect that results from abnormal developmental processes and usually causes a functional deficit
• ex: interatrial septal defect

• a morphological deviation from an assumed standard that causes no function deficit
• ex: persisting median artery

a packageof congenital abnormalities that occurs in several organ systems as a result of a single factor

development of a single individual in structure and function both prenatally and postnatally

• increase in mass
• due to protoplasmic synthesis, uptake of water or intercellular or intracellular deposits
• an increase in size of a living being or any of its parts occuring in the process of development

the modification and specialization of cells, tissue, and organs in structure or function during the course of development

• anlage
• the first appearance of a differentiating structure
• an aggregation of cells in the embryo indicating the first trace of an organ or structure

• a subspecialty of anatomy
• the science of the origin and development of the organism from the fertilization of the ovum to the period of extrauterine life
• is restricted to the developmental processes occuring during the prenatal period of life

• a subspecialty of obstetrics
• encompasses the study, diagnosis, and treatment of the fetus in utero

• maternal/fetal medicine
• a subspecialty of obstetrics involving the diagnosis and treatment of the fetus/newborn from 20th week of gestation until 4 weeks after birth

a subspecialty of pediatrics involving the study, diagnosis, and treatment of the newborn during the first four weeks after birth

• greatest length
• crown-rump length
• crown-heel length
• biparietal diameter

used during embryonic period

• sitting height
• used during embryonic period
• measure from head (crown) to buttocks (rump)

• standing height
• used during fetal period

visible on vaginal ultrasound at approximately 13 days (chorionic villi begin)

visible on vaginal ultrasound at 22+/- 1 day

the diameter of the fetal head as measured from one parietal eminence to the other

• 38 weeks (266 days) counting from the time of fertilization or conception
• used by embryologists (and this class)

true age + 1 day

true age + 1 to 3 days

• true age + 14 days
• 280 days
• used by obstetricians

• true age
• ovulation age
• copulation age
• menstrual/gestational age

• 22 pairs of autosomes
• 1 pair sex chromosomes

23 pairs of chromosomes TOTAL

• 22 autosomes
• 1 sex chromosome

23 chromosomes TOTAL

process of cell differentiation through which a cell gives rise to two daughter cells, each of which is genetically identical to the parent

• process of reduction division of chromosomes
• takes place only in germ cells
• reduces number of chromosomes from a diploid to a haploid state
• consists of two divisions

pupil constriction

• timing
• end products

the sequence of events by which spermatogonia are transformed into mature sperm

• first meiotic division begins at puberty
• results in four haploid mature sperm

spermatid to sperm

• loss of cytoplasm
• gain of tail
• formation of acrosome

sequence of events by which oogonia are transformed into mature oocytes

• first meiotic division begins in early fetal life
• results in one mature ovum

• provide constancy of the chromosome number from generation to generation
• allows random assortment of maternal and paternal chromosomes between the gametes
• allows for crossing over of chromosome segments, producing a recombination of genetic material

a defect in the separation of homologous chromosomes

difference in the number of chromosomes

• hyperactivity of sperm
• changes in surface membrane properties leading to the acrosome reaction

• complex molecular changes that result in perforations in the acrosome
• allows for the release of hyaluronidase and acrosin from the acrosome
• occurs in the female genital tract

• passage of sperm through corona radiata
• penetration of zona pellucida
• zona reaction
• fusion of the plasma membranes of the two gametes
• completion of 2nd meiotic division of the oocytes with fomation of the female pronucleus
• formation of male pronucleus
• fusion of pronuclei forming the diploid zygote

• prevents polyspermia - occurs once the first sperm penetrates the zona pellucida and the ovum
• change in properties of the zona pellucida
• renders it impermeable to other sperms
• results from action of lysozomal enzymes released from cortical granules

• completion of the 2nd meiotic division of the secondary oocyte
• restoration of the diploid number of chromosomes in the zygote
• mixing of paternal and maternal chromosomes to ensure diversity of species
• determination of chromosomal sex
• initiation of cleavage

• day 6
• the blastocyst has made contact with the posterior lining of the uterus

• repeated mitotic divisions of the zygote
• results in a rapid increase in the number of cells (2,4,8,16...)

16 cell stage of division

• the zona pellucida must degenerate for implantation to occur
• the blastocyst implants within the posterior superior wall of the uterus within the functional layer of endometrium
• the trophoblast differentiates into the cytotrophoblast and syncytiotrophoblast

• occurs when fluid secreted within the morula forms a blastocyst cavity
• the inner cell mass becomes the embyroblast (which becomes the embryo)
• the outer cell mass is now the trophoblast (which becomes part of the placenta)

• cytotrophoblasts and syncytiotrophoblasts are formed from the trophoblast
• implantation has begun
• hypoblast (primary endoderm) is formed

• implantation is complete
• formation of the bilaminar embryonic disc
• formation of the chorionic villi
• enough HCG produced for a positive pregnancy test

• primary umbilical vesicle
• hypoblast + exocoelomic membrane

extraembryonic somatic mesoderm + syncytiotrophoblast + cytotrophoblast

• compact layer: densely packed connective tissue around the necks of uterine glands
• spongy layer: edematous connective tissue containing the dilated, tortuous bodies of the uterine glands
• basal layer: blind ends of uterine glands
• compact layer + spongy layer = functional layer

enzyme needed to get sperm through the corona radiata

enzyme needed for sperm to burrow through the zona pellucida

ampulla of the uterine tube

seminiferous tubules - rete testis - efferent ducts - epididymis - vas deferens/ductus deferens - seminal vesicles - ejaculatory duct - penile urethra - vagina - cervix - uterus - fallopian tubes - ampulla

• to assist with high risk pregnancies
• to provide counseling for patients with genetic disorders or family history of genetic defects
• to help prevent complications of labor and delivery with high risk patients

hypertension, HIV, diabetes mellitus, kidney disease, multiple gestations, thyroid disease, advanced maternal age

• maintain good control of medical conditions (tight glucose control)
• take folic acid for prevention of neural tube defects
• stop cigarette smoking and alcohol/drug use
• early prenatal care to ensure good pregnancy outcome!

• abnormal implantation of blastocyst
• not a viable pregnancy
• must be removed from the tube with medication or surgery

dating begins at the time of conception or fertilization

• dating begins from the first day of last menstrual period
• clinical method for dating pregnancies

• estimated due date (for 28 day cycles)
• count back 3 months from last menstrual period and add 7 days

• fertilization until day 56 (end of 8th week)
• all major structures are beginning to form
• crown-rump length can be measured
• most accurate method of dating during this time is by ultrasound

• begins at end of 8th week and ends at birth
• differentiation and growth of organs
• monitor appropriate growth and prepare for delivery
• assessment of fetal age can be determined by a series of measurement called fetal biometry

from birth until 30 days of life

span of time encompassing 24 weeks (viability of fetus) until 30 days post-delivery

defined as the first day of the last menstrual period through the end of the 13th week

• embryonic development (through 8 WGA) is time for organogenesis; highly susceptible to teratogens (alcohol, accutane, etc)
• fetal development (after 8 WGA) body length doubles, skull formation, intestines return to abdomen, sex can be determined at end of the trimester

elevated levels of hCG and progesterone can cause amenorrhea, morning sickness, heartburn, constipation, fatigue, and sinus congestion

• 1st trimester combined testing - serum markers plus ultrasound to test for Trisomy 21 (Down syndrome)
• done between 10 and 13 WGA
• includes pregnancy associated plasma protein-A (PAPP-A), human chorionic gonadotropin (hCG), nuchal translucency on ultrasound (>3.55 indicator of Trisomy 21)
• 85% sensitivity rate with 5% false positive rate

defined as 14-28 weeks gestation

• extensive brain development
• alveoli begin to develop, surfactant secreted
• rapid increase in growth of fetus
• fetal movements at 16-18 WGA
• 24 WGA is considered viability

• 2nd trimester testing - serum markers to test for Trisomy 21 and other genetic defects
• done between 15 and 20 WGA, confirmed by ultrasound dating
• 85% sensitivity rate with 7% false positive rate

• elevated Inhibin A
• decreased AFP
• elevated hCG
• decreased estriol

decrease AFP, hCG, and estriol

increased AFP

a neural tube defect in which  the head of the neural tube fails to close, resulting in absence of a major portion of the brain, skull, and scalp

• "water on the brain"
• accumulation of CSF in ventricles of the brain

the lip and palate failed to fuse in the midline during development

failure of the neural tube to close at bottom

atria are not separated by septum, resulting in 3 chambers of the heart rather than 4

• "double bubble sign"
• duodenum is closed off distally, resulting in air bubbles in the stomach and duodenum

intestines are midline and within a sac outside of the abdominal cavity (fail to return to abdominal cavity during second trimester)

• increase in cardiac output and heart rate
• greatest weight gain
• risk for gestational diabetes
• dermatologic changes - abdominal striae (stretch marks) and melasma (mask of pregnancy)
• increased risk of urinary tract infection due to growth of the uterus

defined as 28 weeks gestations until delivery

• alveoli fully develop for pulmonary maturity
• growth of the fetus continues and can be followed by repeating ultrasound measurements (fetal biometry)

• excessive fetal growth
• defined as >90% for that gestational age
• possible causes include diabetes, prolonged gestation, maternal diet/obesity

• defined as <10% for that gestational age
• constitutionally small
• growth restricted and small
• not small but growth restricted relative to gestational age

• I: inherited - chromosomal or genetic abnormalities
• U: uterus - poor placental perfusion (diabetes, renal disease, lupus) or malformation of the uterine cavity
• G: general - lower socioeconomic status (malnutrition, smoking, alcohol)
• R: rubella - and other TORCH infections

• Toxoplasmosis
• Other infections (syphillis)
• Rubella
• Cytomegalovirus
• Herpes simplex virus

• biparietal diameter
• head circumference
• femur length
• abdominal circumference

• maternal weight gain slows down
• total blood volume peaks around 32 weeks (development of anemia can become more obvious)
• gestational diabetes and pre-eclampsia can occur
• check for palpated fetal movements

refers to a pregnancy that spontaneously ends before a fetus reaches  viability (20-22 weeks gestation)

• 10-15% of clinically recognized pregnancies
• nearly 80% before 12 weeks gestation

• chromosome abnormalities account for about 50% of 1st trimester losses
• nearly 90% of those are at 8 weeks or less

• advanced maternal age
• previous spontaneous abortion
• smoking
• multiparity
• excess alcohol and caffeine intake
• maternal weight - BMI <18 or >25

death prior to delivery or extraction from the mother

if death happens after perceived viability

birth of an infant with signs of life after separation from mother, irrespective of short or long term potential for survival

number of deaths during first year of life per one thousand live births during a given time period

• 10000 live births
• 70 infants die before their first birthday

• 70/10000
• infant mortality rate = 7

• infection: hygeine, handwashing, clean birth conditions, plumbing, HIV control
• resuscitation: knowledge, warmth, "helping babies breathe"
• nutrition: breastfeeding

discrepancy due to both social and medical issues

• congenital abnormalities - spina bifida incidence decreased with folic acid
• prematurity - number has increased
• SIDS - decreased by "back to sleep"
• RDS - decreased through use of surfactant

delivery prior to 38 weeks gestation

delivery from 38-42 weeks gestation

delivery beyond 42 weeks gestation

occurs in infants born AGA at term

• any birth prior to 38 weeks
• survival may occur as low as 23 weeksgestation, but birth at such a gestational age is accompanied by a high risk of mortality and morbidity

• surfactant deficiency
• incomplete alveolar development
• clinically labeled respiratory distress syndrome (RDS)
• pathologically labeled hyaline membrane disease (HMD)
• may evolve over weeks to months to more chronic lung disease - bronchopulmonary dysplasia (BPD)

• poor cardiac function
• hypotension (low blood pressure)
• persistant patent ductus arteriosus

• intraventricular hemorrhage
• immature network of blood vessesls prone to bleeding into the adjacent brain
• diagnosed by head ultrasound

• increased fluid losses
• infection
• low temperature

• liver - jaundice
• blood - anemia
• immunity - increased risk of infection
• eye - retinopathy of prematurity
• ear - hearing loss
• intestine - necrotizing enterocolitis
• kidney - erractic fluid / electrolyte balance
• genitalia - undescended testes, inguinal hernia

born <2500 grams (~5lbs)

born <1500 grams (~3 lbs)

born <1000 grams (~2lbs)

birthweight between 10-90th percentile

birthweight less than 10th percentile

birthweight above the 90th percentile

• pattern of reduced fetal growth which may result in SGA status
• various etiologies which determine long term outcome
• IUGR

• IUGR
• "blueberry muffin" rash
• deaf
• hepatitis
• anemia
• thrombocytopenia

• IUGR
• microcephaly
• abnormal face
• heart murmur - ventricular septal defect (VSD)
• mental retardation

• LGA
• hypoglycemia
• respiratory distress

• AGA
• respiratory distress
• scaphoid abdomen
• heart sounds displaced

• decreased pulmonary vascular resistance
• increased systemic vascular resistance
• blood in pulmonary artery enters lungs instead of ductus arteriosus
• blood in right atrium enters right ventricle instead of going through foramen ovale
• placental circulation ceases

• clinical assesment of transition from intrauterine to extrauterine life
• objective 10 point score of infant's physiologic activity immediately after birth
• 5 items - heart rate, respiratory effort, response to stimulus, muscle tone, color - scored from 0 to 2

term referring to the embryo/fetus and associated extraembryonic fetal membranes

• chorion/placenta
• amnion/umbilical cord
• yolk sac
• allantois

sperm + oocyte

amnion + chorion

• second week of development
• trophoblasts differentiates into two layers - cytotrophoblast & syncytiotrophoblast
• embryoblast forms two layers - epiblast and hypoblast
• extraembyronic mesoderm splits into two layers - somatic and splanchnic mesoderm
• two cavities form - amniotic sac and yolk sac(s)

• sometimes the trophoblast develops and forms placental membranes although little or no embryonic tissue is present
• results in degenerating chorionic villi that form cystic swellings
• secrete high levels of hCG
• most often, the result of an abnormal fertilized egg

3-5% of hydatidiform moles develop into malignant trophoblastic lesions which can spread rapidly through lymphogenous or vascular metastasis

• a single sperm fertilizes an ova with no genetic material in it (result of nondisjunction in meiosis)
• two sperm fertlize an ova with no genetic material in it
• two sperm fertilize an apparently normal ova

• 1/2000 pregnancies (rare)
• 10X more prevalent in Asian women
• higher prevalence in women younger than 17 and older than 30

extraembryonic mesoderm + two layers of trophoblast (cytotrophoblast and syncytiotrophoblast)

syncytiotrophoblast tissue with a core of cytotrophoblast

• invasion of mesenchymal cells at core of primary chorionic villi
• entire chorionic sac is covered with secondary chorionic villi

mesenchyme in core of secondary chorionic villi differentiates into capillaries and associated blood cells

• loosely organized polymorphous pluripotent tissue
• blood vessels and cells frequently develop from this tissue

• "afterbirth"
• the primary site of nutrient and gas exchange between mother and fetus
• fetomaternal organ

• fetal part: develops from the chorionic sac (chorion frondosum)
• maternal part: develops from the endometrium (decidua basalis)

tissue contributions from both fetus and mother

• protection: defends against anything harmful that may be circulating in the maternal blood from crossing into fetal circulation
• nutrition
• respiration: gas exchange
• excretion: getting rid of waste products that build up in high levels of metabolism occuring in the fetus during growth and development
• hormone production: hCG

• the functional layer of the uterine endometrium
• layer that is sloughed off during menstrual flow

• decidua basalis
• decidua capsularis
• decidua parietalis

• forms the maternal part of the placenta
• between the chorionic vesicle and the myometrium

• superficial part of the decidua overlying the conceptus
• closes in over the top of the implanting embryo

remaining endometrium lining the main cavity of the uterus

• cellular and vascular changes in the endometrium that occur as the blastocyst implants
• maternal reaction to the implantation process

• bare, relatively avascular area
• chorion laeve
• chorionic villi cover the entire chorionic sac until the beginning of the 8th week
• villi in the decidua capsularis become compressed, deprived of adequate blood supply, and degenerate

• "clumps" of decidua basalis
• location where the villi are bathed in maternal blood, but fetal/maternal blood will not mix

villi associated with decidua basalis proliferate & branch profusely

• fusion of amnion and smooth chorion
• amniotic sac enlarges faster than the chorionic sac
• ruptures during labor

preterm rupture of amniochorionic membrane

• normally no intermingling of maternal and fetal blood
• deoxygenated blood returns to the mother from the placenta through the two umbilical arteries
• oxygen-rich blood flows from the mother to the placenta through the umbilical vein

• consists of extrafetal tissues separating the maternal and fetal blood
• tertiary villi form stem villi which form branch villi
• the main exchange between mother and fetus takes place through the branch villi

• metabolism - synthesis of glycogen, cholesterol, fatty acids (provides energy for the embryo/fetus)
• transport of gases and nutrients - via simple diffusion, facilitated diffusion, active transport, or pinocytosis
• endocrine secretion - hCG

• not pregnant - uterus in pelvis minor (anteversion)
• 20 weeks pregnant - uterus up to level of umbilicus
• 30 weeks pregnant - uterus up to level of epigastric region

• dilation
• expulsion
• placental stage
• recovery

• discoid
• hemochorial
• maternal surface - attached to uterus, cotyledons
• fetal surface - very smooth, slippery and shiny due to amnion, attached to umbilical cord

minor projection of placenta

• chorionic villi penetrate the full thickness of the myometrium to or through the perimetrium (into peritoneal cavity)
• may require hysterectomy

abnormal adherence of chorionic villi to the myometrium (muscular layer of the uterus)

• placenta covers internal os of uterus
• may cause 3rd trimester bleeding or premature separation of the placenta
• may require C section

• umbilical cord is attached to the amniotic and chorionic membranes not to the placenta
• predispose to tearing hemorrhage

umbilical cord attaches at periphery of placenta

• two arteries: carrying deoxygenated blood
• one vein: carrying oxygenated blood
• surrounded by a large amount of connective tissue (Wharton's jelly)

• too long - prolapse or coil around fetus, possible knots
• too short - premature separation of placenta

• surrounds the embryo/fetus
• gradually enlarges to obliterate the chorionic cavity and forms the epithelial covering of the umbilical cord

• clear watery fluid
• produced in part by amniotic cells but derived primarily from maternal blood

• absorbs jolts
• allows for fetal movement
• prevents adherence of the embryo to the amnion
• acts as a barrier to infection
• permits normal lung development
• acts a temperature regulator
• involved in maintaining homeostasis of fluid and electrolytes

• low volumes of amniotic fluid for a particular gestational age
• can cause fetal abnormalities (eg. pulmonary hypoplasia, facial defects, limb defects) due to mechanical compression of the fetus against the uterine wall

• preterm rupture of the amniochorionic membrane
• placental insufficiency with diminished placental blood flow
• renal agenesis or obstructive uropathy (absence of fetal urine contribution to amniotic fluid reduces the volume)

• high volumes of amniotic fluid
• in excess of 2000 ml when the fetus does not swallow the usual amount of amniotic fluid

• severe anomalies of the central nervous system
• esophageal atresia in which fetus is unable to swallow the amniotic fluid

• set of congenital birth defects
• believed to be caused by entrapment of fetal parts (limbs or digits) in fibrous amniotic bands while in utero
• results from tears in the amnion

• results from fertilization of two oocytes
• DZ twins always have two amnions and two chorions (may be fused)
• hereditary tendency

• have a single chorionic sac
• have separate amnions, but share a placenta
• develop from one zygote by division of the embryoblast (inner cell mass) of the blastocyst

• discordant twins
• there is a shunt of arterial blood from one twin through arteriovenous anastomoses into the venous circulation of the other twin

• thoracopagus = joined in thoracic region
• dicephalic = two heads

• diagnosis of abnormalities in fetal life
• multidisciplinary field, though generally applied in maternal fetal medicine

• early detection of malformations & disorders
• inform and educate of the presence (or absence) of a fetal disorder
• offer choice
• treat the disorder in utero

• family history or prior history of congenital defect, cytogenetic defect, or single gene disorder
• "advanced maternal age"
• abnormal routine ultrasound

• defects present at birth
• does not imply anything about cause or pathology

• chromosomal abnormalities
• diagnosed by visually assessing karyotype

• mutant DNA at the nucleotide level
• diagnosed for molecular techniques

• 33-35+ years old
• refers to the concept that fetal risk for certain disorders increases with increasing maternal age

• maternal meiotic defect
• usually meiosis I (the reduction step)
• aneuploidy

• abnormal chromosome number
• trisomies & monosomies

Down Syndrome

Patau Syndrome

Edward Syndrome

Turner Syndrome

Klinefelter Syndrome

• Down Syndrome (+21)
• Patau Syndrome (+13)
• Edward Syndrome (+18)

• Turner Syndrome (45, X)
• Klienfelter Syndrome (47, XXY)

Trisomy 21 > Trisomy 18 > Trisomy 13

• at 33 yrs - 1/2%
• at 35 yrs - 1%
• at 40 yrs - 2%
• at 50 yrs - 10%

• have no risk for fetal loss
• useful in any pregnancy, even those without any increased risks
• screening methods
• ultrasound
• maternal serum screening (MSS)

• have a risk for fetal loss
• used only if indicated
• diagnostic methods
• chorionic villus sampling (CVS)
• amniocentesis

• transvaginal best at 5-9 weeks
• transabdominal at 17-20 weeks
• standard test ~18-20 WGA
• uses sound waves
• no harm to fetus
• nonstandard enhancements - 3D technology, fetal echocardiography

• neural tube defects (NTDs)
• club foot
• heart defects
• cleft lip

• ambiguous genitalia
• polydactyly
• omphalocele

• nuchal thickness (NT) or edema
• cystic hygroma

• sensitivity varies 20-80% depending on type of defect
• better - NTDs; worse - facial and/or cardiac defects
• best views of fetus not until >16 weeks
• most single gene disorders have no physical malformations (normal prenatal ultrasound)

• tests maternal blood for fetal abnormalities
• compares observed values to expected values
• result given as a ratio - observed/expected
• normal = 1
• units - MoM (multiples of the median)

• 10-13 WGA
• Pregnancy Associated Plasma Protein (PAPP-A)
• human chorionic gonadotropin (hCG)
• combined with ultrasound for nuchal thickness

• low PAPP-A
• high hCG
• high NT
• 85% detection rate

• low PAPP-A
• low hCG
• high NT
• 87% detection rate

• "quad screen"
• hCG: human chorionic gonadotropin
• UE3: unconjugated estriol
• AFP: alpha fetal protein
• DIA: dimeric inhibin A

• high hCG
• low UE3
• low AFP
• high DIA
• 80% detection rate

• low hCG
• low UE3
• low AFP
• 80% detection rate

• high AFP
• 80% detection rate

• low PAPP-A
• high hCG (x2)
• high NT
• low UE3
• low AFP
• high DIA
• 97% detection rate

• low PAPP-A
• low hCG (x2)
• high NT
• low UE3
• low AFP
• 97% detection rate

• carries a false-positive rate in addition to false-negative
• explanation of results time consuming, complex
• calculation of risk relies on accurate maternal data (gestational age, diabetes, ethnicity, etc.)
• screens for only a few disorders

• fetal DNA detectable in maternal blood <9 WGA
• initially available for gender and gender-related conditions
• eventual use in PNDx of fetal aneuploidy will follow

• outpatient procedure
• > 15 WGA
• ultrasound guided percutaneous needle in amniotic fluid
• 30cc of amniotic fluid aspirated
• turn-around time for results = 2 wks
• risk of miscarriage = 1/2 to 1%

• outpatient procedure
• 10-12 WGA
• ultrasound guided percutaneous or transcervical catheter into villi of chorion (tissue biopsy)
• turn-around time for results = 1 wk
• risk of miscarriage = 1%

• chromosomal testing (karyotyping or fluorescence in situ hybridization)
• DNA testing for single gene disorders via molecular techniques
• amniotic fluid AFP testing for open NTDs

• 2% of CVS cytogenic analyses are ambiguous and require a follow up amniocentesis
• many genes/mutations are unknown
• must know gene/mutation of interest to give information about specific disorders
• not routine

• usually isolated birth defect
• >90% detectable with ultrasound
• 80% detectable with 2nd trimester MSS
• diagnosis usually made with noninvasive techniques

• associated with AMA
• risk is 1% at 40 years
• 97% detectable with integrated MSS
• diagnosis is invasive with CVS, AOC

• autosomal recessive, single gene disorder
• #1 lethal inherited disease in caucasians (f508 mutation)
• prenatal diagnosis is invasive via CVS, AOC

• primitive streak formation
• notochord formation
• gastrulation
• formation of three germ layers
• differentiation of mesoderm
• neurulation
• early development of cardiovascular system
• embryonic folding
• early development of gastrointestinal system

• 3rd - 8th weeks of development
• when anlage of all organ systems occur
• when embryo is most susceptible to tetratogens

nervous system (neural tube defects)

• the process in which a gastrula develops from a blastula by the inward migration of cells
• the beginning of morphogenesis
• followed by organogenesis

• bilaminar embryo is converted into a trilaminar embryo
• gastrulation
• the three primary germ layers are established
• the basic body plan is established, including the physical construction of the rudimentary primary body axes
• inductive interactions - hallmark of neurulation and organogenesis

one tissue type induces another tissue type to develop into something

formation of the neural tube, the precursor for the CNS

• anteroposterior
• dorsoventral
• left-right axis

• cells in the anterior (cranial) margin of the embryonic disc
• expresses genes essential for head formation - establish cranial end of the embryo before gastrulation

formation of the primitive streak

• indicative of the anterior-posterior (craniocaudal) axis
• longitudinally oriented streak going from the primitive node to the posterior aspect of the developing bilaminar embryo (cloachal membrane)
• appears as a thickened band of epiblast cells on the dorsal surface of the embryonic disc (characterized by rapid proliferation)
• establishes right/left sides and dorsal/ventral surfaces of the embryo

• Hansen's node
• reflects the craniocaudal axis
• proliferation of epiblast cells  at cranial end of primitive streak

• established by cellular and molecular mechanisms
• primitive streak ventrolizes mesoderm under the influence of BMP4 + FGF
• increased goosecoid expression dorsolizes mesoderm (chordin, noggin, and follistatin inhibit BMP4)

• controlled by a cascade of genes produced by notochord, primitive streak, etc.
• nodal - member of transforming growth factor beta superfamily
• SHH (Sonic Hedgehog) - midline barrier; represses expression of left-sided genes

• formation of the primitive streak
• development of the notochord
• differentiation of three germ layers

• bone morphogenic proteins
• essential in the process of gastrulation

• also called oropharyngeal membrane
• point where hypoblast and epiblast have essentially fused
• forms the mouth

forms the anus

epiblast

• embryonic connective tissue
• ameboid
• loosely organized
• actively phagocytic
• polymorphous
• pleuripotent

• deep surface of epiblast undergoes heavy proliferation to form mesenchyme - mesenchyme forms undifferentiated mesoderm - becomes intraembyronic (embyronic) mesoderm
• some epiblast cells displace hypoblast to form intraembryonic (embryonic) mesoderm
• remaining epiblast cells form intraembryonic (embryonic) ectoderm

• undifferentiated tissue resulting from primitive streak that does not degenerate and disappear by the end of the fourth week
• most common tumor of newborns
• more common in girls than boys
• can be visualized in utero with ultrasound and CT

• primative streak forms mesoderm until early part of 4th week
• length of primitive streak decreases as notochord increases
• primitive streak will eventually degenerate and disappear by the end of the 4th week
• caudal end of embryo will decrease in size

• defines the primordial cranialcaudal axis of the embryo
• provides some rigidity to the developing embryo
• serves at the basis for development of the axial skeletom (bones of the head and vertebral column)
• indicates the future site of the vertebral bodies
• persists as the nucleus pulposis of the intervertebral discs
• primary inductor in the early embryo - induces overlying ectoderm to thicken and form neural plate

• formation of some mesenchyme cells migrating cranially from the primitive node (primitive pit)
• deep to the epiblast (overlying ectoderm)
• grows cranial to the prechordal plate

• where ectoderm is fused with endoderm
• primordium of the oropharyngeal membrane

• primitive pit proceeds cranially into the notochordal process to form the notochordal canal
• floor of notochordal process fuses with underlying embryonic endoderm
• fused layers degenerate - form opening for communication with yolk sac
• notochordal canal disappears & notochordal plate forms
• notochordal cells proliferate & notochordal plate infolds to form definitive notochord

• persistance of proximal notochordal canal
• obliterated when notochord is complete

• rare variant of neuroenteric cyst
• AKA posterior spina bifida, combined spina bifida, neurenteric fistula, dorsal enteric fistula
• primary notochord defect - the notochord is split, but not completely separated from the primitive intestine
• syndrome manifests as a cleft in the dorsal midline of the body through which intestinal segments are exteriorized

• paraxial mesoderm
• intermediate mesoderm
• lateral mesoderm
• extraembryonic mesoderm

• mesoderm formed from epiblast cells migrating (invaginating) through the primitive streak
• mesenchymal intraembryonic mesoderm layer forms between ectoderm and endoderm with notochord down the midline

• striated skeletal muscle
• muscles of the head
• skeleton (except cranium)
• dermis of skin
• connective tissue

• urogenital system
• gonads
• ducts
• accessory glands

• connective tissue
• muscles of viscera
• serous membranes of body cavities
• primordial heart
• blood and lymphatic cells
• spleen
• suprarenal cortex

• continuous with lateral mesoderm
• outside of the embyro itself

• days 20-30
• further development of paraxial mesoderm
• segmenting of embyro
• first appear in future occipital region
• develop craniocaudally

• further development of lateral mesoderm
• formation and fusion of coelomic spaces forms intraembryonic coelom
• intraembryonic coelom splits lateral mesoderm into intraembryonic somatic mesoderm and intraembryonic splanchnic mesoderm

• superior to intraembryonic coelom
• forms body wall and skeletal muscle
• areas innervated via GSE/GSA

• inferior to intraembryonic coelom
• forms smooth muscles of developing gut
• areas innervated via GVE/GVA

• creates neural tube - gives rise to CNS
• creates neural crest - migrates away from dorsal surface of neural tube, gives rise to a diverse set of cell types
• creates definitive epidermis - covers over the neural tube once it is created

the processes involved in the formation of the neural plate and neural folds and closure of the folds to form the neural tube

sonic hedgehog (SHH) from notochord and adjacent mesoderm

notochord induces the ectoderm lying dorsal to it to thick and become neuroectoderm forming the neural plate

• forms the neural plate
• gives rise to the CNS (brain and spinal cord)

blood vessel formation

endothelial tubes fuse to form vessels which fuse to form networks of vessels

mesenchyme cells - angioblasts - blood islands - develop endothelial lined lumen (flattened angioblasts) - cavities fuses to form networks of endothelial channels - vessels sprout by endothelial budding, fuse with other vessels - hemangioblasts develop from endothelial cells of vessels

• endothelial cell precursors
• vessel forming cells

isolated angiogenic cell clusters

blood cells developed from endothelial cells of vessels

angioblastic cords

horseshoe-shaped endothelial-lined tube surrounded by myoblasts

• cardiovascular system
• by the end of 3rd week (on 21st or 22nd day), blood is circulating and heat begins to beat

• 2 arteries: carrying waste from the embryo back to placenta
• 1 vein: carrying oxygenated blood & nutrients to embryo

• folding of the flat trilaminar embyro into a "cylindrical embryo"
• folding in the median (head & tail) and horizontal (right & left) planes

• occur at 21 days
• folding in the medial plane
• pinches embryo off from rostral and caudal end
• helps incorporate the yolk sac into the midgut
• brings heart into its normal location (inferior to oropharyngeal membrane)

• occurs at 26 days
• folding in the horizontal plane
• pinches off embryo from either side
• helps establish the body wall - defines boundaries of intraembryonic coelom

process involved with the formation of the neural plate and neural folds & closure of the folds to form the neural tube

• creates neural tube - anlage to CNS
• creates neural crest cells - give rise to many different cell types
• creates definitive epidermis - covers the neural tube once created

• notochord and adjacent paraxial mesoderm induce the overlying embryonic endoderm to form the neural plate by secreting Sonic Hedgehog
• notochord produces noggin, chordin, and follistatin which block the action of BMP4 - allow the dorsal ectoderm to thicken and become neuroectoderm
• WNT-3a and FGF (fibroblast growth factor) also induce neural plate to form hindbrain and spinal cord

day 18

3rd to 8th week

3rd to 8th week

package of congenital abnormalities that occur in several organ systems as a result of a single factor

• edges of neural plate begin to elevate to form neural folds with an interventing neural groove
• presomite stage

• first pair of somites are seen at paraxial mesoderm
• neural folds become prominent
• somatopleure & splanchnopleure occur
• intraembryonic coelom subdivides into pericardial, peritoneal & pleural cavites

association of somatic mesoderm with overlying ectoderm

association of somatic mesoderm with underlying endoderm

• neural folds are prominent rostrally - first signs of brain development; almost ready to fuse in dorsal midline
• neural crest cells move to either side because of differential growth
• 3 somite stage

• neural ectoderm becomes neural plate which has neural folds and a neural groove in between
• neural folds fuse in midline to form the neural tube which separates it from the surface ectoderm
• cells making up the walls of the neural tube thicken and multiply quickly - undergo specialization to form brain and spinal cord
• neural canal undergoes massive differentiation to form ventricular system in brain

formation of neural tube

secondary cavity formation at the caudal end of the neural tube to form the sacral spinal cord

• lumen of the neural tube communicates with the amniotic cavity through the rostral and caudal neuropores
• openings supply nutrients & energy to embryo

• day 25: anterior (rostral) neuropore closes
• day 27: posterior (caudal) neuropore closes
• closures coincide with establishment of vascualr system

• 4th somite inferiorly
• upwards of the becomes brain

• 5 somite embryo
• Carnegie stage 10

• 13 somite embryo
• Carnegie stage 11

• wall of neural tube is thick, pseudostratified columnar neuroepithelium
• neuroblasts are dividing rapidly
• three neural tube layers develop - marginal zone, mantle zone, ventricular zone
• thin root and floor plate & thick walls form the alar and basal plates

• marginal zone
• mantle (intermediate) zone
• ventricular (ependymal) zone

• deep to meninges (derived from mesnchyme around neural tube)
• mostly consists of fibers (white matter)

• gives rise to majority of neurons
• grey matter, dorsal & ventral horns

• adjeacent to neural canal
• forms ventricular system of the brain & spinal canal

• forms dorsal portion (horns) of mantle
• sensory neurons: receives central processes; gives rise to axons that form ascending sensory pathways

forms ventral horns of the spinal cord (motor neurons, GSE)

• groove that separates the dorsal sensory neurons from the ventral motor neurons
• separates alar plate & basal plate

neural crest cells

• from neuroepithelium
• become different types of neurons as they develop processes - apolar, unipolar, bipolar, and multipolar neurons

neuroepithelial cells differentiate into epemdymal cells when they stop producing neuroblasts

• give rise to glia (support cells that seem to play an important role in the nervous system)
• macroglia: astrocytes & oligodendrocytes (myelination in the CNS)
• microglia: from mesenchye

homeobox-containing transcription factors: Pax-3, Pax-7, Msx-1 and Msx-2 are expressed throughout the neural plate

• notochord gives rise to SHH, which represses Pax-3 and Pax-7, increases expression of Pax-6, and initiates neural tube floor plate formation
• Pax-6 has a ventralizing effect and induces cells on either side of the floor plate to become motor neurons

• overlying surface ectoderm expresses BMP-4 & BMP-7
• dorsalizing inductive effect on adjacent neuroectoderm
• causes increase in Pax-3, Pax-7, Msx-1, and Msx-2
• results in formation of roof plate and alar plate
• stimulates expression of a transcription fact called "slug" in future neural crest cells
• induces formation of sensory neurons in the alar plate after neural tube closure

• spinal or dorsal root ganglion
• adrenal medulla
• mesenchyme - CT in head and neck
• arachnoid & pia - leptomeninges
• cranial nerve ganglia
• melanocytes
• C cells of the thyroid gland
• conotruncal septum in the heart
• schwann cells - myelin in PNS
• oligodendrocytes - myelin in CNS
• glial cells

defects in neural crest cell migration or morphogenesis

Hirschsprung's disease (aganglionic colon)

• aorticopulmonary septation defects of heart
• anterior chamber defects of eye
• cleft lip and/or cleft palate
• frontonasal dysplasia
• DiGeorge syndrome
• certain dental anomalies

• cranial NCC neurocristopathy
• hypoparathyroidism
• thyroid deficiency
• thymic dysplasia leading to immunodeficiency
• defects in cardiac outflow tract & aortic arches

• CHARGE association/ syndrome
• Waardenburg syndrome

a "package" of congenital abnormalities that occur in several organ systems as a result of a single factor

• C: coloboma, failure of choriod fissure to close (pupil has keyhole appearance)
• H: heart defects, Tetralogy of Fallot (most common)
• A: atresi choanae, blocking of airway, cannot breathe through nose
• R: retardation of growth & development, associated with sensory deficits, mental retardation
• G: genitourinary problems, genital hypoplasia, undescended testes, small labia
• E: ear abnormalities, unusally shaped ears, sensory or conductive hearing loss

• autosomal dominant
• family history of parent with Waardenburg syndrome
• extremely pale blue eyes or heterochromia (1 blue & 1 brown)
• partial albinism - white forelock (poliosis) of hair, early greying of hair
• deafness (variable degree)

• pheochromocytoma
• neuroblastoma
• medullary carcinoma of thyroid
• carcinoid tumors
• neurofibramatosis

tumor of chromaffin tissue of adrenal medulla

tumor of adrenal medulla and/or autonomic ganglia

tumor of parafollicular (calcintonin-secreting) cells of the thyroid

tumors of enterochromaffin cells of digestive tract

• von Recklinghausen disease
• peripheral nerve tumors

lack of melanocytes (derivative of NCCs)

• both derive from NCC
• schwann cells: myelinate PNS; one schwann cell surrounds one axon
• oligodendrocytes: myelinate CNS

about the 5th week

• may be caused by alteration in morphogenesis or histogenesis of nervous tissue
• may be caused by developmental failures occuring in associated structures (notochord, somites, mesenchyme, & skull)
• failure of closure of the neural tube
• occurs most commonly in regions of the anterior & posterior neuropore

• closure defect of the spinal cord
• results in chronic infection, motor & sensory deficits, disturbances in bladder function

closure defect in the area of the brain

• defective closure of the neural tube during the 4th week
• defects of dorsal induction OR neural tube defects (NTDs)
• also involve overlying tissue - meninges, vertebral arch, muscles & skin
• NTDs are caused by genetic and/or environmental factors

• nonfusion of the embyronic halves of the vertebral arches
• pedicles & lamina don't meet up

• spina bifida occulta
• spina bifida cystica
• spina bifida cystica with meningocele
• spina bifida cystica with meningomyelocele
• spina bifida cystica with myeloschisis

• indicates with region of closure of the caudal neuropore at the end of the fourth week
• indicated by a posterior skin dimple in the median plane of the sacral region

• defect in neural arch
• failure of the embryonic halves of the arch to grow normally & fuse in the median plane
• occurs in L5 or S1 vertebrae in about 10% of otherwise normal people
• may be indicated by a small dimple or a tuft of hair
• usually produces no clinical symptoms

• involves protrusion of the spinal cord and/or meninges through a defect in the vertebral arch
• called "cystica" because of cyst-like sac that is associated with these anomalies
• occurs once in every 1000 births

• when the sac contains meninges and cerebrospinal fluid
• the spinal cord and spinal roots are in the normal position
• usually no clinincal deficits

• the spinal cord and/or nerve roots are included in the sac
• often associated with a neurological deficit below or inferior to the level of the protruding sac
• may occur anywhere along the vertebral column, but are most common in the lumbar region

• spinal cord is open because the neural folds failed to close in the fourth week
• monitor alpha-fetoprotein levels, nutritional & environmental factors (vitamins & folic acid)

• first trimester - spinal cord extends the entire length of the body
• after 8 weeks - vertebral column develops more rapidly than the spinal cord
• spinal roots are anchored in place, elongate at the column lengthens
• cauda equina: elongated lumbar and sacral roots
• lumbar cistern: expanded portion of the subarachnoid space

• mesoderm: particularly in the axial skeleton
• neural crest cells: give rise to mesenchyme in head & neck (contributes to the skull)

lies on either side of the notochord between notochord & intermediate mesoderm

• gives rise to urogenital system
• "intermediate mesoderm of Swartz"

• becomes separated by coelomic spaces
• coelomic spaces will join to form the intraembryonic coelom
• divides into somatic mesoderm & splanchnic mesoderm

• blocks of segmented paraxial mesoderm
• develop during days 20-30
• appear (cranial to caudal) as bead-like elevations on the dorsolateral surface on either side of the developing neural tube
• direct correlation with number of somites & age of embryo
• 20 days: 1-4 somites
• 25 days: 17-20 somites
• 30 days: 34-35 somites

associated with the ectoderm

somatic mesoderm + ectoderm

associated with endoderm

• splanchnic mesoderm + endoderm
• will eventually contribute to the formation of the muscular walls of the gut

• dorsolateral dermomyotome
• ventromedial sclerotome
• both are found on either side of the developing neural tube (will become spinal cord)

• dermatome: becomes dermis of the skin
• myotome: becomes myoblasts (muscle precursors)

schlerotome: will become vertebrae and ribs

• SHH: causes the ventral part of the somite to form schlerotome
• PAX1: controls chondrogenesis and vertebral formation
• PAX3: demarcates the dermomyotome
• Wnt proteins + Myf5: form epaxial (deep) back muscles

• Sonic Hedge Hog
• secreted by notochord & floor plate of neural tube
• causes basal cell plate to become motor neurons
• causes ventromedial part of somite to form sclerotomes & express PAX1

• family of development control genes that encode nuclear transcription factors
• PAX1: controls chondrogenesis & vertebral formation
• PAX3: demarcates the dermomyotome

• endochondral: mesenchyme becomes ossified to form cartilagenous precursor; cartilage will then be ossified to become bone
• intramembranous: mesenchyme forms directly to bone

differentiates into various structures depending upon its positioin & type of joint

• ex - elbow joint, knee joint
• interzonal mesenchyme differentiates into different parts of the synovial joint according to location
• peripheral: IM forms capsular & other associated ligaments
• centrally: IM will undergo apoptosis & form the joint cavity
• lining central cavity & articular surfaces: IM forms synovial membrane

IM may form hyaline cartilage at costochondral junctions OR fibrocartilage in the pubic symphysis joint

• ex - sutures of the skull
• IM will become dense fibrous connective tissues

• skull, vertebral column, ribs, sternum
• develops from schlerotome during 4th week under influence of PAX1

• on either side of the notochord (form vertebral column)
• surrounding the neural tube (form vertebral column)
• in the body wall (form ribs)

• cranial: loosely arranged part
• caudal: densely arranged part

• most cranial portion of densely arranged cells - forms portion of the intervertebral disc (annulus fibrosis)
• caudal portion of densely arranged cell - fuses with loosely arranged cells of next caudal sclerotome to form centrum of vertebral body (embryonic body of the vertebrae)
• notochord in region of intervertebral disc - form nucleus pulposus (surrounded by annulus fibrosis)
• rest of notochord - associated with centrum of developing vertebrae; will degenerate under normal circumstances

very malignant, rapidly epanding tumor resulting from failure of notochord to degenerate

• lie at the level of the intervertebral disc
• lie across the articulation between two adjacent vertebrae (neural foramina)
• allow movement of spinal cord
• muscles must cross over a joint to be effective (except facial muscles)

• centrum forms surrounding notochord
• costal process sticks out into body wall
• vertebral foramen contains neural tube
• surrounding neural tube is vertebral arch

• vertebra with chondrification centers (endochondral bone formation associated with areas of sclerotome)
• one on each side of notochord
• one on each costal process
• one on each half of vertebral arch

• cartilaginous precursor gets primary ossification centers
• vertebrae become bony - process regulated by HOX genes
• one center surrounding notochord in centrum
• one center on either half of vertebral arch
• "napoleonic" vertebrae: three bony parts

• mesenchyme around neural tube vertebral (neural) arch
• mesenchyme in body wall forms costal processes that form ribs in the thoracic region (forms transverse process in other regions)
• "napoleonic" vertebrae - centrum & two halves of vertebral arch
• neurocentral joint between two halves of the arch

• between two halves of "napoleonic" vertebrae
• analogous to epiphyseal plate in long bones
• accomodates the still expanding neural tube & spinal cord

during the first 3-5 years

• evolutionarily conserved genes
• found in all vertebrates
• involved in early embryonic development & specify identity and spatial arrangements of body segments
• code for proteins which bind to DNA & form transcriptional factors which regulate gene expression

• accessory ribs in lumbar & cervical regions
• congenital hemivertebra
• spina bifida

• results from development of costal processes in lumbar or cervical region
• usually located in lumbar region - often asymptomatic in this area
• cervical rib syndrome

• accessory cervical rib
• typically on C7
• can put pressure on brachial plexus and/or subclavian vessels
• symptoms - pulse weaker on one side
• one reason for thoracic outlet syndrome

• aplasia
• costal processes can fuse with each other

• often accompanies cervical rib formation
• occurs if one of the two chondrification centers on either side of centrum fails to develop
• may be caused by HOX gene mutation
• one cause of scoliosis (lateral curvature of the spine)
• in thoracic region - associated with abnormalities of the ribs (aplasia)

• spina bifida occulta
• spina bifida cystica with meningocele
• spina bifida cystica with meningomyocele
• spina bifida cystica with myeloschisis

location of healed meningocoele or atretic meningocoele

• results from failure of fusion of the halves of the vertebral arch
• marked externally by a dimple or tuft of hair
• lower thoracic, lumbar, & sacral regions are most common (but cervical also possible)

• 6 weeks
• sternal plates converge at ventral midline
• sternal plates fuse in a cranial to caudal direction
• sternal plates become segmented into different sections (sternebrae)
• development produces variations in xiphoid process (bifid, perforated, etc.)
• endochondral bone formation

• pigeon chest: results from overgrowth of ribs; sternum protrudes forward
• cleft sternum: results from incomplete fusion of sternal plates at midline
• notching of xiphoid process: can be bifid
• sternal foramen: sometimes occurs at the junction of 3rd & 4th sternebrae
• ectopia cardis: form of cleft sternum; associated with herniation of thoracic viscera (heart)

• congenital defect of the diaphragm
• NOT a problem with the sternum itself
• diaphragm has a small central tendon attached to xiphoid process
• if pulled excessively, lower end of sternum is greatly depressed

• 5 weeks: mesenchymal condensations
• 6 weeks: chondrified
• 8 weeks: begin to ossify

• by 12 weeks, primary ossification centers have appeared in all bones of the limbs
• secondary ossification centers have appeared in the distal femur & proximal fibula during 9th month of pregnancy
• all other seconday ossicification centers appear after birth

• lateral plate mesoderm: skeleton, tendons, ligaments, vasculature
• somites (dermomyotome): musculature
• neural crest: schwann cells, dorsal root ganglia, sensory axons
• neural tube: motor axons

regulate the types and shapes of bones in the limb

• apical ectodermal ridge: thickened ectodermal clumb of cells at tip of developing limb
• limb formation is under control of fibroblast growth factors
• upper limb develops before lower limb
• "progress zone": highly active mitotic cells that cause lateral expansion of limb away from axis; maintained by FGF4 and FGF8
• 5 weeks: digital rays appear
• 6 weeks: chondrification centers appear
• 8 weeks: various ossification centers form

• FGFR-1: Pfieffer syndrome
• FGFR-2: Pfieffer syndrome, Apert syndrome, Crouzon syndrome
• FGFR-3: achrondroplasia

• mutations in FGFR1 & FGFR2
• craniosynostosis
• broad great toes & thumbs
• cloverleaf skull
• underdeveloped face

• craniosynostosis
• underdeveloped face
• syndactyly (fused hands or feet)

• craniosynostosis
• underdeveloped face
• no hand or foot defects

• forms by intramembranous ossification
• ONLY tubular bone which does this
• later becomes endochondral ossification
• begins to ossify before any other bone in the body

• congenital absense or incomplete formation of clavicle
• can touch shoulders together
• autosomal dominant

• hypoplastic chondrodystrophy
• impairment of cartilage development in the epiphyseal plates of bone
• most common cause of dwarfism
• autosomal dominant (FGFR3)
• 1/10000 occurance rate
• short limbs, large head, normal trunk, muscles develop normally, results in skin folds on thighs

• all muscles of the body develop from the mesoderm
• except the muscles of the iris, which develop from the ectoderm of the optic cup
• striated muscles of the trunk: develop from myotomes (part of somite)
• smooth muscle & cardiac muscle: develop from splanchnic mesoderm

• epaxial division: epimere; supplied by dorsal rami of spinal nerves; develop into deep back muscles
• hypaxial division: hypomere; supplied by ventral rami of spinal nerves; gives rise to muscles in limbs & body wall

• palmaris longus - most common occuring
• trapezius
• serratus anterior
• quadratus femoris
• pectoralis major - part of Poland syndrome (lack of axillary fold)
• abdominal muscles - Prune belly syndrome

• 48 days: limbs extend ventrally, hand and foot plates face each other
• 51 days: upper limbs bent at elbows & hands curved over thorax
• 54 days: soles of feet face medially
• 56 days: elbows now point caudally & knees cranially
• upper limbs rotate 90* laterally so that thumbs enter anatomic position
• lower limbs rotate 90* medially so that big toes enter anatomic position

area of skin supplied by a single spinal nerve at its ganglion

• peripheral nerve field
• area of skin supplied by a peripheral nerve

24 to 42 days after fertilization

• amelia: complete absence of limbs
• meromelia: partial absence of limb or limbs
• syndactyly: failure of tissue between the digital rays to degenerate

• occurs during 4th or 5th week
• development is cranial to caudal, so upper limb development occurs about two days before lower limb
• apical ectodermal ridge interacts with mesenchyme to form "progress zone", forming hand & foot plates
• digital rays form, then tissue in between breaks down to form digits

• genetic: some cases of polydactyly, syndactyly, brachydactyly, etc are autosomal dominant disorders; many limb defects are components of genetic syndromes
• teratogenic: drugs & chemicals (thalidomide, dimethadione, retinoic acid, cadmium), viruses (ex. Rubella), radiation, hypothermia, & hyperthermia
• mechanical: amniotic bands may cause disruption or amputation of part of a limb; fetal compression due to oligohydramnios; uterine defect

• brachydactyly: abnormally short digits
• hypoplasia of thumb
• polydactyly: supernumerary finger or tow
• partial duplication of foot or thumb
• cleft hand or foot: absence of central digits (Lobster claw deformity)
• syndactyly: cutaneous or osseous failure of tissue between digital rays to degenerate
• bilateral talipes equinovaris: club feet; twice as frequent in males (1/1000 births)

• ichthyosis: fish-like skin; failure of superficial epidermis to slough off (keratinization)
• hemangioma/angioma: vascular anomalies; can be treated with laser therapy
• port-wine stains: type of hemangioma; capillary deformation producing characteristic area of red or purple skin

• occurs in 6th week
• mammary ridges: extend from axilla to groin
• mammary glands develop from pair of mammary ridges
• primordium invades mesenchyme, forms modified sweat gland
• development occurs continuously
• notable development at puberty and pregnancy

• polymastia: extra breast; occurs along mammary ridge line
• macromastia: abnormally large breast
• micromastia: one breast is significantly smaller than the other
• polythelia: extra nipples; occurs on mammary line; can occur in males

angioblastic cords in cardiogenic area (evident at 18 days)

• angioblastic cords canalize to form two endocardial heart tubes
• lateral folding of the embryo causes endocardial heart tubes to fuse & form primitve heart tube

22 or 23 days after fertilization

• primordial myocardium: external layer of embryonic heart formed by splanchnic mesoderm; becomes myocardium (muscular wall of heart)
• cardiac jelly: gelatinous connective tissue secreted by myocardium separating external layer from internal layer
• primordial endocardium: internal endothelial layer; becomes endocardium

• truncus arteriosus: continuous cranially with aortic sac (from which aortic arches arise)
• bulbus cordis: gives rise to conus arteriosus & conus cordis (smooth parts of R & L ventricles)
• primitive ventricle
• primitive atrium
• sinus venosus: drains umbilical, vitelline & common cardinal veins

• umbilical veins: carry well oxygenated blood from placenta
• vitelline veins: return poorly oxygenated blood from yolk sac
• common cardinal veins: return poorly oxygenated blood from body of the embryo

• bulbus cordis & primitive ventricle grow faster than other regions
• heart bends upon itself
• ventricles grow inferior & to the left
• venous portion grows superio & to the right
• as heart elongates & grows, it invaginates into the pericardial cavity

• completely envelopes heart
• dorsal mesocardium: initial mesentery suspension of heart to dorsal wall
• transverse pericardial sinus: remnant of dorsal mesocardium; communication between R & L sides of cavity

blood from sinus venosus - primordial atrium - sinuatrial valves - atrioventricular canal - primordial ventricle - bulbus cordis - truncus arteriosus - aortic sac - aortic arches - dorsal aortae for distribution to embryo

• shifts from center to right side; grows & becomes
• sinus venarum: smooth part of R atrium
• coronary sinus
• oblique vein of L atrium

• displaced anteriorly on right
• becomes right auricle

MAGICALLY sprout from future L atrium

• myocardium & cardiac jelly induce endocardium to rapidly divide
• endocardial cushions form on dorsal & ventral walls of AV canal
• tissue is invaded by mesenchymal cells; AV endocardial cushions fuse
• divides AV canal into right & left
• endocardial cushions function as AV valves

• septum primum: grows from roof of primitive atrium to endocardial cushion; forms foramen primum
• foramen primum closes with continued growth of septum primum as foramen secondum appears
• septum secondum grows adjacent to septum primum (becoming wall of R atrium); forms foramen ovale
• septum primum partially degrades; becomes valve of foramen ovale (prevents backflow of blood allowing bypass of R ventricle in utero)

• muscular IV septum: formed by median muscular ridge in floor of ventricle; grows toward AV cushions but leaves IV foramen open
• membranous IV septum: formed by fusion of three compartments - right & left bulbar ridges & endocardial cushion; closes IV foramen
• merges with spiraling aorticopulmonary septum (allows communication between pulmonary trunk & R ventricle; ascending aorta & L ventricle)

• atrial septal defects
• membranous septal defects

• muscular VSD: hole in muscle as it grows up from floor
• membranous VSD: endocardial cushion does not grow up all the way to IV septum at superior portion (severe)

• can occur anywhere foramen occur
• patent foramen ovale
• defect in muscular/membranous portion of septum

• interatrial septum never fuses
• no right/left atria (just one)

• spiraling aorticopulmonary septa doesn't come down
• both ventricles empty into a common trunk
• poorly oxygenated blood goes to lungs & heart
• essentially - one hole opens to common ventricle

• overriding aorta: dextro-position of aortic valves in L & R ventricles
• pulmonary stenosis: narrowing of pulmonary trunk
• ventricular septal defect
• right ventricular hypertrophy

• 1st & 2nd mostly regress
• dorsal aorta between 3rd & 4th degenerate
• 5th degenerates or never forms
• distal portion of right 6th degenerates (why left & right recurrent laryngeal nerves have different positions)

• right: becomes trapped under right subclavian artery with degeneration of right 6th aortic arch
• left: stays below ductus arteriosus

• umbilical vein - ligamentum teres
• ductus venosus - ligamentum venosum
• foramen ovale - fossa ovalis
• ductus arteriosus - ligamentum arteriosum
• umbilical arteries - superior vescial arteries & medial umbilical ligaments

• postductal: after ductus arteriosus; body experiences decrease in blood flow; collateral circulation develops in utero
• preductal: before ductus arteriosus; flow to upper & lower extremities is fine; only at birth does body register inadequate blood flow in descending aorta; unable to develop good collateral flow

• right dorsal aorta does not obliterate at 6th aortic arch
• trachea & esophagus trapped between arches
• transient occlusion during contractions

• normally goes left
• right dorsal aorta persists (left dorsal aorta obliterates)
• hopefully ductus arteriosus develops on right side
• if ductus arteriosus persists on left side, retroesophageal right arch of aorta will trap esophagus & trachea

• carries oxygenated blood from placenta
• right umbilical vein obliterates
• left umbilical vein anastomoses with ductus venosus to drain into IVC

• shunts blood from umbilical vein to IVC
• allows oxygenated blood to bypass the liver in utero

• allows blood to flow in between atria
• bypasses right ventricle in utero

• allows blood to flow from pulmonary trunk to descending aorta
• bypasses lungs in utero

originates from aorta rather than right brachiocephalic trunk

• failure to close at birth
• allows unoxygenated blood into descending aorta

pharyngeal arches - respiratory diverticulum - laryngotracheal groove - laryngotracheal diverticulum - larynx, trachea, bronchi, & lung

• tracheoesophageal septum
• larynx
• trachea (bronchi, lungs)

• 6 pairs
• lined by endoderm on internal aspect
• ectoderm on external aspect
• mesenchymal core (NCCs have invaded mesoderm)

• region in which lung development occurs
• first sign of respiratory system development (4th week)

caudal to 4th pharyngeal pouch

internal space between pairs of pharyngeal arches

• growth of mesenchyme ventral & inferior to pharynx
• endoderm: pulmonary epithelium, glands of lower respiratory tract
• splanchnic mesoderm: connective tissue, cartilage, smooth muscle of trachea & lungs

• cranial end of LT diverticulum differentiates
• endoderm: laryngeal epithelium
• 4th & 6th pharyngeal arches: arytenoid swellings, laryngeal cartilages, mesoderm & neural crest cells

• derived from 4th & 6th pharyngeal arches
• on either side of laryngeal inlet
• occlude passage through larynx into trachea for a time during development
• remodel/ "recanalize" during 10th week

• arytenoid cartilages
• epiglottis
• true & false vocal cords

• ventral aspect of 3rd & 4th pharyngeal arches
• forms hypopharyngeal eminence
• cranial - give rise to tongue
• caudal - epiglottis

• bounded by mucous membranes
• vesitubular folds
• vocal folds

• caudal end of LT diverticulum differentiates
• endoderm: tracheal epithelium & glands, pulmonary epithelium
• splanchnic mesoderm: tracheal cartilage, connective tissue, tracheal smooth muscle

enlargement at distal end of LT diverticulum

• respiratory bud
• main stem primary bronchi: L & R
• secondary (lobar) bronchi: 2L & 3R
• tertiary (segmental) bronchi/bronchopulmonary segments: 8L & 10R

• pseudoglandular: 6-16 weeks
• canalicular: 16-26 weeks
• terminal sac: 26 weeks to birth
• alveolar stage: 32 weeks to 8 yrs

• Lungs resemble exocrine glands with ducts
• Cuboidal epithelial tissue in endoderm
• Surrounding mesenchyme contains blood vessels & fibroblasts (collagen CT)
• Terminal bronchioles & all major lung elements present EXCEPT no means by which respiration can occur

• Cranial portion of developing lungs mature faster than caudal portion
• Lumen of bronchi enlarge
• Terminal bronchioles enlarge and branch → respiratory bronchioles
• Respiratory bronchioles divide into 3-6 passages (alveolar ducts) with terminal sacs (primordial alveoli)
• Massive vascular proliferation in mesenchyme-          Differentiation of type I and II pneumocytes
• RESPIRATION POSSIBLE (though not efficiently)

• Respiratory bronchioles enlarge & divide
• Epithelium of endoderm becomes more squamous-          Growth of capillary network → capillaries bulge into terminal sacs lined by type I pneumocytes (Blood-air barrier; provides adequate gas exchange)
• Collagen & elastic fibers are deposited by endoderm
• Type II pneumocytes present in high numbers → secretion of pulmonary surfactant

• Genuine mature alveoli begin to form
• Mesenchyme differentiates – elastin & collagen; smooth muscle cells
• Squamous epithelial layer of endodermal cells
• Thin type I pneumocytes, type II pneumocytes → secreting lots of surfactant
• Capillaries bulge into aveolar sacs
• GAS EXCHANGE through alveolocapillary membrane

• adequate thoracic space
• fetal breathing movements
• adequate amniotic fluid

• needed for lungs to expand & grow
• if inadequate, lungs will be smaller than normal

• fetus ingests amniotic fluid, aspirates it into lungs & expels it against resistance
• conditioning respiratory muscles
• critical for normal development & maturation of lungs

• too little amniotic fluid
• fetal breathing movements don't occur

• too much amniotic fluid
• fetus does not recycle amniotic fluid
• caused by tracheoesophageal fistula or esophageal atresia

• Abnormal communication between structures
• Problem in the formation of the tracheoesophageal fold/septum

• Esophagus ends as a blind sac
• Every time swallowing occurs, material is aspirated into trachea
• Food vomited back up shortly after ingestions

• Ventral trachea is not separated from dorsal esophagus
• Fusion of tracheoesophageal fold/septum does not occur along entire length

• Failure of larynx to “recanalize”
• Prevents ingestion of amniotic fluid for lung development

• congenital high airway obstruction syndrome
• negatively impacts lung development - can't ingest & aspirate amniotic fluid
• partial cause - laryngeal atresia

small outgrowth of trachea in cervical region

• liver has passed through diaphragm
• restricts thoracic space, lungs fail to grow properly

• hyaline membrane disorder
• type II pneumocytes die
• not enough surfactant produced
• causes rapid, shallow breathing; cyanosis