2.5 Developmental Pathology

GM2 Gangliosidosis- Tay Sachs Disease

Tay Sachs Disease Deficiency of hexosaminidase A Accumulation of GM2 Gangliosides* (Glucocerebroside and sphingomyelin) Eastern European Ashkenazi Jews 1/30 carrier rate Severe brain involvement- progressive mental, motor deterioration, ataxia, blindness, dementia, death by 3yo *Cherry red spot- storage of neurons in retina Wide sulci, narrow gyri. Progressive loss of CNS.

Congenital Syphilis

The WHO estimates worldwide, "1.36 million have active syphilis" If untreated, 1/2 pass infection to fetus 520,000 adverse pregnancy outcomes from syphilis annually Exposure before 4th month of gestation - no infection because treponemes do not invade the placental tissue or fetus until 5th month

Agenesis

The complete absence of organ/part of organ.

Niemann- Pick Disease

(Pick the right ZebraSphelgomyelinase, pick one with big Spleen HSM) Sphingomyelinase deficiency Accumulation of sphingomyelin "zebra bodies" in fixed tissue macrophages, neurons **Organs most affected: brain, spleen, liver, bone marrow, lymph nodes, lungs Cherry red spot in 1/3 Common in Ashkenazi Jews Severe infantile form- Massive HSM, failure to thrive, psychomotor deterioration Whorled and zebra body storage in brain, spleen, liver, nodes, marrow and lungs

Congenital Syphilis Symptoms- Early vs Late

(hepatoSplenomegaly, Spots on hands and Soles, Snuffles-rhinitis, Saddle nose, Saber shin, hutchinSon Triad) Early- Before 4 months, no infection Intrauterine/perinatal death 25% Large placenta, hydrops HepatoSplenomegaly, hepatitis Anemia, thrombocytopenia Rhinitis*, bullous rash on palms, soles*. Snuffles with runny nose. Uveitis, glaucoma Periostitis, osteochondritis Pneumonia Untreated congenital Syphilis (face/head) Hutchinson triad- Hutchinsons teeth (notched), interstitial keratitis (inflamed cornea), 8th nerve deafness (meningovascular infection) Saddle Nose- Bridge of nose destroyed by osteochondritis Saber Shin- Periostitis with new bone causes anterior bowing

Glycogenosis Type II- Pompe Disease

(pompous- heart, liver muscles- Glucoside- side chick) Only GSD that has deficiency of enzymes in lysosomes Alpha 1,4 Glucosidase (acid maltase) deficiency leads to accumulation of glycogen in lysosomes Lysosomes store glycogen- Heart, liver, muscle Cardiomegaly Hepatomegaly Hypotonia Death in infancy or childhood unless treated with ERT (heart, skeletal muscle and liver need glycogen and so they develop these things because of increased glycogen in cells)

What is Down Syndrome?

*Most common chromosomal disorder Trisomy 21 (3 copies of 21) Major cause of mental retardation in US 1/700 US newborns have DS Increases with moms age - meiotic nondisjunction

Cytomegalovirus CMV

*Most common fetal viral infection Usually asymptomatic- 95%, we only know a person has it because they make antibodies Highest risk in 2nd trimester, making malformations less frequent - Damage to already formed organs - CNS, middle ear deafness, anemia, microcephaly, hepatosplenomegaly, chorioretinitis, cerebral periventricular calcification,thrombocytopenia - Microscope- tubular epithelial cells with large intranuclear inclusions, clear nuclei, condensed nuclear membrane. Captain CMV

Example of Deformation

- EX- clubbed feet are deformation of extremities, tallies

What does Gaucher disease look like in microscope?

- Large cells, wrinkled tissue paper cytoplasm Streaky appearance to cytoplasm- Gaucher Cells Wrinkled tissue paper cytoplasm- streaky nature Glucocerebrosie accumulates as big stringy rods

Turner Syndrome

Webbed nick, widely spaced nipples, no breast, multiple pigmented nevi. No mental retardation Streak Ovary Hydrops fetalis Fetal cystic hygroma- becomes webbed neck Aortic coarction and bicuspid aortic valve Horseshoe kidney 45X- 99% are nonviable Single most common cause of increased mortality in children with this disorder- Cardiovascular abnormality

Glycogenosis Type II Pompe Disease Microscopic morphology

Normal muscle has normal sarcoplasm and nucleus. In Pompe disease theres marked clearing where glycogen was. Clear represents marked glycogen storage in cells. Hypotonia Accumulation of glycogen in cells with Pompe disease

Etiology of Birth Defects

Ones we have most effect on are Adverse intrauterine environment- (Nurture) Teratogens, Birth trauma, Maternal disease Genetic disease- (Nature)Singe gene defects, Chromosomal defects Combined genetic/environmental

Ectopia

Organ or cells outside of normal location Ectopia courdis- defect in sternum so the heart is ectopic- outside of thorax.

What are two maternal diseases that can be teratogenic?

PKU and diabetes

Trisomy 13

Patau Syndrome Bilateral cleft lip Polydactyly Rocker Bottom feet Robertsonian translocation This karyotype contains a robertsonian translocation. Recall that a robertsonian translocation chromosome is derived [der] from the long arms [q] of two acrocentric chromosomes fused to each other at the centromere(s) [centromere = band 10]

Thalidomide Embryopathy

Recognized by Lenz in 1961 in Europe after epidemic of phocomelia. 50-80% of mothers exposed to thalidomide early in gestation had infants with phocomelia Thalidomide is sleeping aid for pregnant women.

Hypoplasia

Reduced size* due to incomplete development of all or part of an organ How does one lung fail to develop? Congenital Diaphragmatic Hernia with agenesis of the left hemidiaphragm and hypoplasia of the left lung. Agenesis of left hemidiaphragm results in unilateral pulmonary hypoplasia. Infants with genesis of left hemidiaphragm and resultant diaphragmatic hernia. Abdominal contents from one side of abdomen herniate up into left hemithorax, impairing development of left lung and get hypoplasia

Malformation

Structural defect, present at birth, due to abnormal development (week 3-10) Primary error in morphogenesis- happened as its forming, from begining- teratogen or genetic malformation Intrinsic (genetic) or extrinsic (teratogen) Can affect one or multiple organs Examples - congenital heart malformation, neural tube defect, cleft lip/cleft palate

What happens in normal morphogenesis?

• Cell migration • Cell proliferation • Cell-cell interactions among different tissues (e.g., ectoderm and mesoderm) • Cell-matrix interactions • Programmed cell death (apoptosis) • Hormonal and mechanical influence

Osteogenesis Imperfecta clinical presentation

• Multiple bone fractures • Short stature • Deafness • Translucent blue sclera - abnormal collages makes them more translucent • Type II OI infants die in utero or shortly after birth

Why does Fetal ALcholos Syndrome affect fetuses?

Fetal hypoxia during maternal binge drinking may be important Acetaldehyde (EtOH metabolite) interferes with cell migration?

DiGeorge Syndrome

Newborn has transposition of great vessels, facial dysmorphism, prominent nose and micrognathia, T cell immunodeficiency and hypocalcemia. Absence of thyme shadow Chromosome 22q11.2 22q11 deletion One micro deletion

In Erythroblastosis Fettles, what is the name for the CNS lesion?

Kernicterus Unconjugated bilirubin has an affinity for lipids and binds to lipids in the brain. The immature blood brain barrier contributes to entry of bilirubin into the CNS in infants

What does Gaucher disease cause?

Liver and spleen Hepatosplenomegaly, pancytopenia due to hypersplenism Gaucher cells in spleen, liver, marrow, nodes, lungs Erlenmeyer Flask Deformity - Storage + macrophage activation - Enzyme replacement treats

Torch Infections

Fetal infections (teratogen) can present with TORCH- Toxoplasmosis Other (Syphillis) maybe ZIka Rubella Cytomegalovirus Herpes Classic findings- microcephaly, cerebral calcification, mitropthalmia, chorioretinitis, conjunctivitis, cataract, heart disease, hepatomegaly and jaundice ,petechia and purport, pneumonitis

Neurofibromatosis Type 1 von Recklinghausen Disease

1/3000, most common AD trait* 100,000 NF patients in US Half sporadic, half inherited- inherited pass it on *Variable expression, 100% penetrance Gene on 17q encodes protein **neurofibromin, which is a negative regulator of the p21 ras oncoprotein. Neurofibromin normally suppresses the activity of the ras oncoprotein, but with *loss of suppression of the ras protein* due to mutation in NF gene, there may be uncontrolled ras activation which can predispose to formation of neurofibromas

Incidence of Birth Defects

120,000 US babies/year have birthdefect 3% - major congenital anomaly 10-15% - minor congenital anomaly- Often face, neck or hands- don't interfere with kids life 50% of infant/childhood mortality in US is due to birth defect

Factors associated with SIDS

3 month old, boy, history of cold, soft mattress, 18 yo mom, prone sleeping, mother smoked, father uses marijuana, slightly preterm

Neurofibrosarcoma

3-5% of NF 1 patients develop neurofibrosarcoma (Malignant peripheral nerve sheath tumor) MPNST

When does SIDS happen? How should babies sleep

90% during first 6 months of life, 2-4 months Supine position (on back) not prone

Lysosomal Storage Disease

A mutation causes a defect in synthesis of lysosomal enzyme with resultant reduced activity or reduced amount leading to a metabolic block and accumulation of substrate in lysosome with decreased/altered cell function. Organ effected depends on where most of the material stored is normally degraded. Progressive* organ, cell dysfunction - Hepatosplenomegaly - CNS dysfunction - Bone dysplasia - Death in childhood

What is a coarction of the aorta?

A narrowing or intimal ridge at the "aortic isthmus", distal to left subclavian artery, proximal to the ductus arteriosus.

Dysplasia

Abnormal cellular organization. Dysplasia, (Dys place is Disorganized) Classic Example- Renal dysplasia- complete disorganization, can't see cortex or medulla and see cysts. Microscope has cysts everywhere, don't see glomeruli or tubules. See islands of cartilage- associated with renal dysplasia

Deformation and example

Abnormal form, shape, or position Due to mechanical force (uterine constraint*- push on face- was normal, but over time mechanical force alters development) Usually arises later than malformation (week 10-40) Less recurrence risk in sibs - From 34-38 weeks gestation, fetal growth is greater than uterine growth and there is a decrease in the amount of amniotic fluid making compression deformations more common at end of pregnancy

Aplasia

Absence of an organ, but presence of primordial tissue or anlage (theres A Plase for it) Aplasia of globes in infant with Congenital Rubella

What are the different types of Birth Defects?

Agenesis Aplasia Hypoplasia Atresia Dysplasia Ectopia

Fetal Alcohol Syndrome

Alcohol- most common teratogen. Leading preventable* cause of mental retardation Dose response usual, not always-threshold? Most severely affected infants born to chronic alcoholics No safe amount, no safe time, no safe type 2/1000 US babies Fetal hypoxia during maternal binge drinking may be important Acetaldehyde (EtOH metabolite) interferes with cell migration?

Type II Mucopolysaccharidoses

All are autosomal recessive except Hunter Syndrome (Type II) which is an X linked trait, almost never in females. Males are hunters *Typically don't have corneal clouding Type II Hunters= vision

Anticonvulsants

All have teratogenic risk- Hard to take mother off during pregnancy 2-3x risk of malformation in baby of epileptic mother Growth deficiency, mental retardation, hypertelorism (eyes close), distal phalangeal and nail hypoplasia.

Trisomies

All trisomies are syndromes Most common are T21, T18 and T13 Down syndrome patients survive best, but theres better survival chancer for T13 and T18 than there used to be

Example of Disruption

Amniotic band sequence destroys digit. Shortened digits are asymmetric***two sides of the body different. May cause amputation. Fetus is entangled in torn amniotic membrane. Fetal surface has shreds of amnion Same recurrence chance as normal population. - Many cases- Baby in amniotic sac, tear in membrane, baby extends arm through area and gets tangled in the tearing. Get ischemia (tightening as baby grows), leading to destruction of part and limb reduction deficit (disruption) - Placenta has shreds of amnion on surface. - Face can tangle in amnion too, wrestler with no arms or legs

Oligohydramnios (Potter) sequence

Amniotic fluid (AF) volume is maintained by fetal urine production. It cushions the fetus and contributes to normal lung growth If the kidneys don't develop (renal agenesis/bilateral renal dysplasia) or if the urinary tract is obstructed (urethral atresia) there is a decrease in urine production and a resultant decrease in AF. Also occurs because of prolonged ruptured fetal membranes with chronic leaking of AF and in uteroplacental insufficiency With decreased AF volume, the Potter phenotype develops, the uterus compresses fetal limbs and face and the lungs fail to develop since lung growth in utero is dependent on a normal amount of AF. Lower extremities show positional deformation and the child's face is deformed with a flat, beak like nose and small chin. Biggest problem- Bilateral pulmonary hypoplasia**** Nodules on surface of placenta- Amnion nodosum*

What findings have been described in the CNS in infants with SIDS? What is the most common cause of sudden unexpected death in infants who rule out SIDS?

Astroliosis of the brain stem and cerebellum, hypoplasia of the arcuate nucleus or a decrease in brain stem neuronal populations Infections (viral myocarditis of bronchopneumonia) most common sudden "unexpected" death, followed by unsuspected congenital anomalies

Osteogenesis Imperfecta

Autosomal Dominant "Brittle Bone Disease" Abnormal Type I collagen synthesis Deficiency of normal bone matrix Type I-IV OI express clinical/genetic heterogeneity, but they all affect synthesis of Type I collagen which causes deficiency of normal bone matrix Abnormal amount of protein or wrong synthesis

Single Gene Defects

Autosomal dominant- variable symptoms and penetrance (1 copy of abnormal). Manifested in heterozygotes. - Osteogenesis Imperfecta - Von Recklinghausen Disease Autosomal recessive - early symptoms, often mutation in gene for enzyme (2 copies of abnormal). Manifest in homozygotes. - Lysosomal storage diseases - Cystic Fibrosis Symptoms early in life, gene encodes for structural protein or lysosomal storage disease

How can we prevent Erythroblastosis Fetalis>

By giving the mother Rhesus immune globulin (RhIg) containing anti D antibodies within 72 hours of delivery of the first fetus and at 28 weeks gestation during this pregnancy

What percent of congenital anomalies are caused by fetal infections?

Cause 2-3% of congenital anomalies. Viruses (Rubella, CMV, herpes, varicella zoster, influenza, HIV, Enterovirus) can be teratogenic

What are teratogens that cause birth defects?

Chemical, physical, biological agent that lead to fetal death, growth retardation, developmental anomaly, functional impairment Susceptibility varies depending on the dose and timing. Specific for a developmental stage and each teratogen has a specific mechanism. Preventable

What do Teratogens cause and how?

Chemical, physical, biological substances that can cause fetal death, growth retardation, anomaly Susceptibility varies- dose dependent and specific for developmental stage Preventable! In most cases Teratogens act by interfering with embryonic and fetal cellular growth, proliferation, migration and differentiation. Occurs through interaction of the agent with a specific receptor/s at developmentally susceptible stages

Mucopolysaccharidoses Clinical Features

Coarse facial features Clouded cornea Skeletal and joint dysplasia (short stature, hands flexed) dysostosis multiplex Hepatosplenomegaly Cardiac valve sclerosis and subendothelial coronary artery deposits- MPS accumulates in subendothelial cardiac Mental retardation Some have macroglosia AV Valves have thickened, rolled edges- sometimes stenotic

Maternal cocaine use

Cocaine (coke constricts) a vasoconstrictor, decreases uterine blood flow, fetal oxygenation Placental abruption, premature rupture of membranes Spontaneous abortion, stillbirth, prematurity, IUGR *SIDS **In nursery: Intracerebral bleeding, necrotizing enterocolitis Prematurity, low birth weight, microcephaly, long term cognitive deficits and developmental delay.

Chromosomal Abnormalities and Fetal Loss

Common in early pregnancy loss 50% of pregnancies are lost 50% of those lost in first months of pregnancy have chromosomal abnormality 1% of live-born infants have chromosomal abnormality

Why is the PKU girl blonde with blue eyes?

Competitive inhibition of phenylalanine for tyrosinase in melanocytes. Patients with PKU have a diffuse pigmentary dilution due to elevated levels of L phenylalanine resulting form a deficiency in the enzyme L phenylalanine hydrolase that converts L phenylalanine to L tyrosine. The high levels of phenylalanine provide competitive inhibition for tyrosine.

Pathology of Down Syndrome

Congenital Heart Disease - 40% - Endocardial cushion defects including osmium primum ASD, AV valve malformation, VSD - ASD- Atrial Septal Defect - VSD- Ventricular Septal Defect - Atrioventricular canal Leukemia - 10-20x increased risk - Acute lymphoblastic leukemia - Acute myeloid leukemia including acute megakaryoblastic leukemia Alzheimer's Disease after 40 yo - 100% Flat facies, broad nasal bridge, epicentral folds, Brush field spots (white spots on iris), oblique palpebral issues, abnormal palmar creases, mental retardation, congenital heart malformations (ASD, VSD, endocardial cushion defects, including atrioventricular canal), megacolon, growth failure. Diamnionic dichorionic

Birth defects

Congenital anomalies (present at birth) Abnormality or disorder that may be due to abnormal gene or acquired injury

Tay sachs microscope

Cortical neurons with extended

Disruption and Example

Destruction of normal body region/organ Caused by extrinsic force Not inherited, no risk or recurrence Accident**

Microscopic MPS Features

Distention of lysosomes- filled with undegraded substrate Accumulated GAGs in lysosomes.

Trisomy 18

Edwards Syndrome Prominent occiput (back of head) micrognathia (small lower jaw) Generalized muscular hypertonia Rocker bottom feet Horseshoe kidney with multicystic dysplasia*

Types of Teratogens

Environmental cause of birth defect Drugs- Illegal or legal Infectious (viruses, syphilis) Irradiation Maternal diseases- PKU, Diabetes mellitus

What do we do for kids with Lysosomal Storage Disorders?

Enzyme replacement therapy Supportive care Substrate reduction therapy Bone marrow transplantation Gene Therapy

Autosomal Recessive Traits

Everyone has several AR genes- manifest in homozygotes Expression and penetrance uniform* Symptoms begin early in life Often due to mutation in gene that encodes an enzyme - **1/2 of normal amount of enzyme results in normal phenotype

Atresia

Failure to form a lumen. Duodenal or tracheal atresia

Congenital Rubella Infection

German measles, RNA virus Maternal Rubella vaccination reduces infection rate in newborns Virus teratogenic effect is a function of gestational age at infection, very teratogenic before 12-16 wks gestation Depending on malformation rate, it can be as high as 50% - At 3-11 wk infection rate 100%- High rate of malformations - At 26 wk infection rate 25%- Malformations uncommon (Rubella, Right away!) Causes intrauterine death, spontaneous abortion

Important Lysosomal Storage Diseases

Glycogenosis- Type II, Pompe Disease Tay Sachs Disease Gaucher Disease - survive into adulthood Neimann Pick Disease Mucopolysaccharidosis - MPS I - Hurler Syndrome

Syndromes

Groups of congenital anomalies with one cause Ex- Fetal Alcohol Syndrome, Down Syndrome, CMV infection Result of chromosomal abnormalities- Down Syndromes (trisomy 21) , Edwards Syndrome (3 copies of 18), Patau Syndrome (3 copies of 13)

Lysosomal Storage Disease Mechanism

Have complex substrate, taken up by lysosome. In it there are many lysosomal enzymes that do different steps, until finally we get small diffusible end products. In LSD we are missing an enzyme, so the complex macromolecule is not degraded and accumulates filling the lysosome. Increased substrate interferes with cellular function leading to clinical presentation- lysosomal distention has wide ranging effects. Progressive disease because progressive storage.

Transposition of the Great Vessels

Heart Malformation Transposition of the great vessels Ventricular septal defect

Ventricular Septal Defect

Heart malformation Small muscular VSDs are the most likely to close spontaneously 50%. Increased volume and pressure load presented to the right ventricle and pulmonary circulation causes pulmonary hypertension and, ultimately, a reversal of the early left-to-right shunt to a right-to-left shunt, resulting in delivery of poorly oxygenated blood to the systemic circulation. In utero, the pulmonary circulation is a low-flow, high-resistance circuit. At birth, the lungs expand, and the lungs and pulmonary arteries become high-flow, low-resistance circuits. Pulmonary vascular resistance is normally much lower than the resistance of the systemic circulation. In fluid systems, flow is greatest along the path of least resistance. If a large VSD is present, left ventricular blood will follow the path of least resistance, and a certain percentage will be shunted into the right ventricle and pulmonary arteries. The clinical effects and functional significance of a VSD depend on its size. VSDs that are smaller than the aortic orifice have limited left-to-right shunts because the defect itself has some intrinsic resistance. Small ones, especially those less than 0.5 cm, are often very loud and can close spontaneously. These children are generally asymptomatic and have normal chest radiographs and EKGs. Larger defects offer essentially no resistance to flow. They remain patent and allow a significant left-to-right shunt. Patients with large undiagnosed or uncorrected VSDs are at risk to develop secondary pulmonary vascular changes, chronic persistent elevations of pulmonary vascular resistance, and, eventually, right heart failure. The left ventricle and left atrium also experience volume overloading and hypertrophy. The media and intima of this small pulmonary artery are markedly thickened. The lumen of the vessel is much smaller than normal. This anatomic change is a consequence of the progressive increase in pulmonary blood flow that accompanies a large VSD. At some point, these small vessel changes become irreversible, even if the VSD is repaired.

Maternal Phenylketonuria (PKU)

If phenylalanine levels are elevated in mom with PKU during gestation. This can cause mental retardation, microcephaly, congenital heart disease(NOT CHF), growth retardation, spontaneous abortion in heterozygote infant. Baby has mousy/musty smell from phenylacetic acid. Baby is most likely heterozygote and won't be effected, but exposed to it can result to symptoms like PKU Mom has low levels of PAH- Takes Phenylalanine to Tyrosine

Tetralogy of Fallow

In congenital rubella infection VSD, Dextroposed aorta, pulmonary stenosis lead to RVH- right ventricular hypertrophy, acquired change working it harder Baby is cyanotic***

Mucopolysaccharidoses

MPS1= Hurler Syndrome Deficient enzyme needed for degradation of glycosaminoglycans GAGs (dermatan sulfate, heparan sulfate, keratan sulfate, chondroitin sulfate) GAGs are in extracellular matrix Clinically progressive* - Mentally Retardation - Dysostkosis multiplex- skeletal Type I II** III IV VI VII, each defined by deficiency in enzyme in GAG degradation. All are autosomal recessive except for Type II Hunter Syndrome is X linked trait, almost never in females.

Neural tube defect

Malformation

Autosomal Dominant Description

Manifested in heterozygotes Trait can be inherited or from a new mutation in gamete Variable penetrance, expressivity Decreased Penetrance- Clinically normal child with gene Variable Expressivity- If symptoms due to mutation vary- if a trait is present in all children with gene but expression is different Genes that encode structural proteins*, metabolic pathway regulation* subject to feedback control are defective

Drugs as Teratogens

Many drugs are teratogenic, cause <1% of congenital malformations Thalidomide, folate antagonists, androgenic hormones, alcohol*, anticonvulsants, warfarin, retinoic acid Each drug produces a specific pattern of defects

What are Adverse Intrauterine Environment caused by Maternal Disorders?

Metabolic disease (e.g., diabetes, PKU, advanced age, obesity) Maternal drug use Maternal infection Radiation or chemical exposure Birth Trauma (adverse environment=potentially preventable)

Mercury Poisoning Minamata Disease

Methyl Mercury- Neurotoxin to developing CNS Damage follows exposure any time during gestation. Inhibits division and migration of neuronal cells, and disrupts architecture of developing brain. Clinical presentation is "Cerebral Palsy", microcephaly, **cerebral atrophy, developmental delay Some fish contain lots of mercury, avoid them while pregnant.

Type II Osteogenesis Imperfects

Missense mutation in gene for alpha-1 chain of type I collagen Die in utero or shortly after birth Synthesis of abnormal collagen molecules interferes with formation of normal fibrillar triple helix structure Positional deformation of lower and upper extremities. Fractures of almost all long bones.

Gaucher Disease

Most common LSD* (GauCher, GluCoCerebrosidase) Glucocerebrosidase deficiency Glucocerebrosidase cleaves glucose residue from ceramide. Its an important part of cell membranes. Need to catabolize glucocerebroside and if we don't have enzyme it accumulates in fixed tissue macrophages. *Accumulate glucocerebroside in fixed tissue macrophage system* Distended cells called Gaucher Cells Treated with ERT

Birth defects from multifactorial disorders

Multifactorial- Genetics + Environment Run in families- recurrence risk of this is higher than the risk of a disorder in the general population but lower than the risk for monogenic disorder Many have unknown etiology Multiples genes and environment. - Congenital Heart Malformations - Neural Tube defect - Cleft Lip/palate

Sequence and Example

Multiple congenital anomalies are secondary to one primary abnormality Malformation + resultant deformations Initiating event may be a malformation, deformation or disruption. Example: Oligohydramnios (Potter)sequence-

What is the mechanism for edema in Erythroblastosis Fetalis?

Rh incompatibility occurs when an Rh-negative mother is impregnated by an Rh-positive father. The result can be an Rh-positive baby. In such a case, the baby's Rh antigens will be perceived as foreign invaders, the way viruses or bacteria are perceived. The mother's blood cells attack the baby's as a protective mechanism that can end up harming the child. If the mother is pregnant with her first baby, Rh incompatibility is not as much of a concern. However, when the Rh-positive child is born, the mother's body creates antibodies against the Rh factor, which will attack the blood cells if she becomes pregnant with another Rh-positive baby.

Erythroblastosis Fetalis/ Hemolytic Disease of the Newborns

Rh incompatibility occurs when an Rh-negative mother is impregnated by an Rh-positive father. The result can be an Rh-positive baby. In such a case, the baby's Rh antigens will be perceived as foreign invaders, the way viruses or bacteria are perceived. The mother's blood cells attack the baby's as a protective mechanism that can end up harming the child. If the mother is pregnant with her first baby, Rh incompatibility is not as much of a concern. However, when the Rh-positive child is born, the mother's body creates antibodies against the Rh factor, which will attack the blood cells if she becomes pregnant with another Rh-positive baby. Rh incompatibility occurs when an Rh-negative mother is impregnated by an Rh-positive father. The result can be an Rh-positive baby. In such a case, the baby's Rh antigens will be perceived as foreign invaders, the way viruses or bacteria are perceived. The mother's blood cells attack the baby's as a protective mechanism that can end up harming the child. If the mother is pregnant with her first baby, Rh incompatibility is not as much of a concern. However, when the Rh-positive child is born, the mother's body creates antibodies against the Rh factor, which will attack the blood cells if she becomes pregnant with another Rh-positive baby. Negative/Positive refers to the presence/absence of the "Big D" rh antigen

Congenital Rubella Syndrome

Rubella virus causes intrauterine death, spontaneous abortion and congenital rubella syndrome. The earlier in the month the mother was infected, the greater the malformation rate Microcephaly, PDA, Cataracts

Congenital Rubella Infection Presentation

Ruby red spots and Red heart- Tetralogy of Fallot + other heart problems, + Robby- diabetes) Microcephaly, cataracts, deafness, microphthalmia, Glaucoma, strabismus, chorioretinitis, petechia and purpora Growth retardation- Continues in neonate Congenital heart malformation- PDA (patent ductus arterioses), pulmonary valve, artery sclerosis, VSD, ASD *Tetralogy of Fallow- VSD, Dextroposed aorta, pulmonary stenosis lead to RVH- right ventricular hypertrophy, acquired change working it harder In pancreatic islets. Infection associated with decreased insulin secretion, leads to overt diabetes.

Can SIDS diagnosis be made if autopsy has not been performed?

SIDS is "the sudden death of an infant under 1 year of age which remains unexplained after a thorough case investigation including complete autopsy, exam of death scene and review of clinical history"

Genetic Disease as an Etiology of Birth Defects

Single gene defect of chromosomal defect 25% of birth defects due to abnormal genetic code Numerical chromosomal anomalies - Trisomies, monosomies 1% of newborns - 50% of spontaneous abortions. Numeric abnormalities over expressed in children lost early Inherited monogenic (single gene) defects- Neurofibromatosis, cystic fibrosis

What is the clinical presentation of fetal alcohol syndrome?

Spontaneous abortion Intrauterine, postnatal growth retardation, mental retardation, emotional disorders Decreased number of neurons, small brain, microcephaly Behavioral abnormalities and growth deficiency Facial dysmorphology (short palpebral fissures, maxillary hypoplasia, flat filtrum, thin upper lip) Short filtrum- completely flat Cardiac Septal defects

Classification of LSD

There are multiple lysosomal storage diseases Categories are defined by substrate that accumulates in lysosome Individual diseases within each group are defined by specific enzyme deficiency 1/7,700 children

Errors in morphogenesis- timing

Timing is everything Preimplantation stage, wk 1-2 - All or nothing. An injurious environmental agent damages enough cells that conceptus dies or surviving pluripotent cells replace those lost and development continues. Lost pregnancy may be unrecognized by mom. Implantation and organogenesis - Wk 3-9, especially wks 4-5 - Very susceptible to injury, malformation. This is when organs are forming. - Malformation Second and third trimester- 10-40 weeks - Injury occurs - deformation, disruption. Injuries are different kind - Deformation and disruption

What other congenital heart malformations cause cyanosis in the newborn?

Transposition of the great arteries, tricuspid atresia, total anomalous pulmonary venous connection and trunks arteriosus

Pathology of Neurofibromatosis

Tumors- Cutaneous neurofibromas, plexiform neurofibromas, meningiomas, optic gliomas, pheochromocytoma, rhabdomyosarcoma, Wilms' tumor, neurofibrosarcoma (Malignant Peripheral Nerve Sheath Tumor - MPNST) 3-5% of NF 1 patients develop neurofibrosarcoma (Malignant peripheral nerve sheath tumor) Six + Cafe au last spot Lisch nodules (pigmented iris hamartomas)

Osteogenesis Imperfecta types

Type I OI (most common) - only 1/2 normal amount pro collagen synthesized Type II, III, IV OI - Type I procollagen gene mutations Each of 3 collagen chains must be normal for collagen triple helix assembly, stability. With 1 bad chain, normal trimers don't form, amount of collagen is deficient. The mutant allele causes a dominant negative effect

Radiation Exposure

Uncommon today 10-50 r in 1st trimester - Diagnostic X ray (<10r) little risk Causes Fetal microcephaly, *blindness, skull defects, *spina bifida, *leukemia, *brain tumors

Tardive Syphilis

Untreated Congenital Syphilis Hutchinson's Triad - - Hutchinson's teeth (notched) - Interstitial keratitis (inflamed cornea) - 8th nerve deafness (meningovascular infection) Treat pregnant mother with penicillin= eliminates fetal infection. Saddle Nose- Osteochondritis causes bridge of nose to be destroyed Saber Shin- periostitis with new bone causes anterior bowing

Retinoid Embryopathy

Used for severe acne Retinoic acid exposure. Spontaneous abortion. *CNS, cardiac, craniofacial defects. - Microtia, anotia- M is a congenital deformity where the pinna (external ear) is underdeveloped. A completely undeveloped pinna is referred to as anotia. - Cardiac defects Characteristically involve the ear! Cleft lip/palate, conotruncal cardiac defects and spontaneous abortion.

Causes of Death in Mucopolysaccharidoses

Valvular stenosis, and subendotheilal arterial deposits in the coronary arteries lead to myocardial ischemia. Myocardial infarction and cardiac decompensation are important causes of death.