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Congenital Anomalies
"born with". Are anatomical defects that are present at birth, but some
are not apparent until years later (cardiac/renal anomalies)
Most common cause of mortality in the 1st year and 1/33 babies are born
with congenital defect.
Definitions
o Malformations- errors in morphogenesis. Intrinsically abnormal
developmental process. Due to gene single gene or chromosomal
defect. Can affect one organ or several
o Disruptions- secondary destruction of organ or body that was previously
normal in development. Extrinsic disturbance in morphogenesis.
Can be caused by environmental agents and is not heritable,
with risk of recurrence in subsequent pregnancy
e.g= amniotic bands- rupture of amnion with formation of 'bands'
which can compress and attach to fetus
o Deformation- Extrinsic disturbance of development. Common, affect 2%
of newborns. Generally due to compression of fetus by abnormal
mechanical forces = structural abnormalities.
E.g.= uterine constraint- bigger fetus (35-38 weeks) outgrows
uterus and there is a relative amount of amniotic fluid decrease
= excessive compression = deformation
Factors that can cause compression
Maternal - first pregnancy, small uterus, malformed
uterus, leiomyomas
Fetal/placental- oligohydromas, multiple fetus,
abnormal fetus
o Sequence- a cascade of anomalies triggered by one initiating aberration.
Eg. Single aberration in organogenesis that sets into motion
secondary effects in other organs
Oligohydramnios (decreased amniotic fluid) which
can be due to renal agenesis, amniotic leak, maternal
hypertension----> result in fetal compression----->
causing:
o altered facies
o positional abnormalities of hands/feet
o Pulmonary hypoplasia
o Amnion nodosum (nodules in amnion)
o Malformation syndrome- cannot be explained by one aberration but
due to single etiologic agent (virus or chromosome abnormality)
which affects several tissues.
o Agenesis- complete absence of an organ and its associated primordium
o Aplasia- absence of an organ due to failure of growth of the existing
primordium
o Atresia- absence of an opening, usually of a hollow visceral organ (eg
intestine)
o Dysplasia- abnormal cellular organization
Causes of anomalies
o Genetic causes- can be chromosomal or single-gene mutations
Chromosomal abnormalities- generally all chromosomal
abnormalities are associated with congenital malformation.
Chromosomal disorders arise during gametogenesis so are not
familial. Common ones include
Trisomy 21, klienfelter syndrome, turner syndrome
Single gene mutations- have mendelian pattern of inheritance;
may involve loss of function in genes that drive organogenesis
or development
Eg- Hedgehog signaling pathway and defects of
forebrain and midface (holoprosencephaly)
10 - Diseases of Infancy + Childhood
o Environmental causes- caused by viruses, drugs, and irradiation
Viruses- can include cytomegalovirus or rubella
Drugs/chemicals- teratogens include thalidomide, folate
antagonists, androgenic hormones, anticonvulsants, and 13-cis-
retinoic acid (used for acne)
Alcohol- can cause fetal alcohol syndrome ( growth
retardation, facial anomalies; microcephaly, short
palpebral fissures, maxillary hypoplasia)
Tobacco- spontaneous abortions
Maternal Diabetes Mellitus- maternal hyperglycemia
induced fetal hyperinsulinemia causes:
o fetal macrosomia (increased body fat, muscle
mass, organomegaly), cardiac problems, CNS
problems which are similar to diabetic
embryopathy
o Multifactorial inheritance- most common. Effects of environmental
influence + 2 or more genes of small effect. Can cause:
Cleft lip, cleft palate, neural tube defects
o Pathogenesis- 2 general principles of development are relevant:
Timing of prenatal teratogenic insult has an important
impact on the occurrence and type of anomaly produced.
Human development can be divided into 2 phases: A)
embryonic period, first 9 weeks of pregnancy B) fetal period
terminating at birth
Early embryonic period (first 3 weeks)- an agent can
either cause enough cell damage to cause death OR it
injures only few cells, which can be recovered without
defects
o Between 3-9 weeks- embryo is extremely
susceptible to teratogenesis (esp. 4-5 weeks).
Organogenesis occurs during this period.
Fetal period- occurs after organogenesis. Has
reduced susceptibility to teratogenic agents. Instead,
fetus is susceptible to growth retardation or injury to
already formed organs.
o ****therefore different anomalies at different
times of gestation.
Interplay between environmental teratogens and intrinsic
genetic defects exemplified by the fact that feature of
dysmorphogeneis caused by environmental insults can often be
recapitulated by genetic defects in the pathways targeted by
these teratogens. Examples:
Cyclopamine- plant teratogen which is an inhibitor of
Hedgehog. Cyclopamine usage produces the same
abnormalities as Hedgehog mutation abnormalities
(holoprosencephaly and cyclopia- single fused eye)
Valproic acid- disrupts Homeobox proteins (HOX).
Valproic acid embryopathy mimics same anomalies
which are seen in HOX mutations (limbs, vertebrae,
craniofacial anomalies)
Vitamin A (retinol) derived all- trans-retinoic acid
o This is essential for development and
differentiation and absence of it can affect
multiple organ development
o BUT, excess (due to acne medications) can
cause retinoic acid embryopathy= CNS,
cardia, craniofacial defects like cleft lip and
palate
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Anomalies due retinoic acid
mediated dysregulation of TGF-B
o Therefore, TGF-B knockout= same
anomalies as retinoic acid embryopathy.
FETAL HYDROPS
Fetal hydrops=accumulation of edema fluid in the fetus during intrauterine
growth
o Generalized edema= hydrops fetalis
Usually lethal
o Localized edema examples
Isolated pleural and peritoneal effusion
Postnuchal fluid accumulation= cystic hygroma
Usually compatible with life
Immune Hydrops
o A hemolytic disease caused by blood group antigen incompatibility
between mother and fetus
Major antigens that cause this are Rh antigen (especially
the D antigen) and ABO blood groups
o Etiology and pathogenesis
Rh- mother is exposed to fetus with Rh+ RBCs creation
of antibodies against Rh antigen
IgM made with first exposure/pregnancy, but its
too big and cant cross the placenta
IgG made during subsequent pregnancy can pass
through the placenta destroys and removes
fetuss RBC anemia, hydrops, extramedullary
hematopoiesis (hematopoiesis occurring outside
bone marrow), jaundice, kernicterus (CNS
damage due to excess bilirubin)
Factors that influence the immune response to Rh+ RBCs
Simultaneous ABO incompatibility: fetal RBCs that
cross into the maternal circulation get removed by
anti-A or anti-B IgM antibodies no or less Rh+
RBCs for mothers immune system to react to
Dose of Rh antigen: antibody response depends
on how much of the Rh antigen the mother is
exposed to
10 - Diseases of Infancy + Childhood
oSignificant transplacental bleed (>1mL of
Rh+ fetal RBCs) hemolytic disease
Treatment and detection
Treatment:
o Rh- mothers are given RhIg at 28 weeks
and within 72 hours of delivery
Also given to mothers after
abortion
o Intrauterine hemolysis: treated by fetal
intravascular transfusions via the
umbilical cord and early delivery
Detection:
o Amniocentesis
o Chorionic villus and fetal blood sampling
o Cloning of RHD gene determines fetal
Rh status in maternal serum
ABO incompatibility and hemolytic disease
Less severe than hemolytic disease caused by Rh
antigen. Why?
o Anti-A and anti-B IgM antibodies made
against fetal RBCs cant cross the
placental, therefore cant attack RBCs
within the fetus
o Neonatal RBCs dont express blood
group antigens A and B that well
doesnt lead to a strong immune reaction
o Other fetal cells express A and B
antigens. These cells absorb some of the
few transferred antibodies from the
mother, saving some of the RBCs
ABO hemolytic disease normally occurs in infants
of group A or B who are born of group O mothers
o Group O mothers have IgG antibodies
directed against group A or B antigens
without prior sensitization
First pregnancy can be affected
No effective protection against ABO reactions,
BUT lysis of infants RBCs is minimal
Consequences of hemolytic disease in neonates
Anemia
o Mild hemolysis increased RBC
production back to near normal levels
o Severe hemolysis hypoxic injury to
heart and liver cardiac
decompensation/failure and decreased
plasma protein synthesis decreased
oncotic pressure (effect of decreased
plasma proteins) and increased
hydrostatic pressure (due to cardiac
failure) generalized edema hydrops
fetalis
Jaundice
o Hemolysis production of unconjugated
bilirubin that passes through infants
blood brain barrier bilirubin binds to
lipids in brain kernicterus/CNS damage
Nonimmune Hydrops
o Main causes
10 - Diseases of Infancy + Childhood
Cardiovascular defects intrauterine cardiac failure
hydrops
Chromosomal anomalies
Turner syndrome, trisomies 21 and 18 structural
cardiac anomalies hydrops
Cystic hygromas (post nuchal fluid accumulation)
seen in Turner syndrome due to abnormalities of
lymphatic drainage from the neck
Fetal anemia
Not caused by Rh or ABO-associated antibodies
Caused by alpha-thalassemia (deletion of all four
alpha-globin genes)
o Most common cause of nonimmune
hydrops
o Commonly seen in SE Asia
Caused by parvovirus B19
o Virus goes into erythroid precursors
(normoblasts) replicates apoptosis of
red cell progenitors decreased
production of RBCs
Twin-to-twin transfusion
One twin gets most of the blood
o Morphology box
Hydrops associated with fetal anemia fetus and placenta
are pale; hepatosplenomegaly secondary to cardiac failure
and congestion
Erythroblastosis fetalis
The presence of A LOT of immature red cells
(e.g., reticulocytes, normoblasts and erythroblasts)
in peripheral circulation due to increased
hematopoietic activity
o Increased hematopoietic activity takes
place in both the bone marrow
(compensatory hyperplasia) and
extramedullary locations (liver, spleen,
lymph nodes, kidneys, lungs, heart)
This doesnt happen in
parvovirus-associated red cell
aplasia)
Kernicterus
CNS damage due to fetal hydrops leading to
increase in bilirubin from hemolysis
Brain is enlarged, edematous and is stained a
bright yellow color internally (mostly the basal
ganglia, thalamus, cerebellum, cerebral gray
matter and spinal cord)
Neural damage occurs at blood bilirubin level
>20mg/dL in term infants; lower if premature infant
o Clinical features
Minimally affected infants
Pallor, hepatosplenomegaly, mild jaundice
More severe cases
Intense jaundice, generalized edema, neurologic
injury
Tx
Phototherapy (converts unconjugated bilirubin
excretable, nontoxic dipyrroles
10 - Diseases of Infancy + Childhood
Total exchange transfusion of the infant in severe
cases
INBORN ERRORS OF METABOLISM AND OTHER GENETIC DISORDERS
Inborn errors of metabolism=genetic abnormalities that lead to metabolic
disorders
o Usually inherited as autosomal recessive or X-linked traits
Phenylketonuria
o Classic PKU
Pattern of inheritance: autosomal recessive
Mechanism: defect of phenylalaninhydroxylase (PAH)
Linked to mutation of PAH gene
Results: buildup of phenylalanine (hyperphenylalaninemia)
5x more above the normal level of phenylalanine
Clinical features:
Onset: not immediately after birth, but after a few
weeks
Musty odor of infants sweat and urine, seizures,
mental retardation, light color hair and skin,
eczema
Females PKU pts can be clinically asymptomatic
o Might still have hyperphenylalaninemia
due to not following diet restrictions
Maternal PKU=Children born
from these female pts can be
mentally retarded, microcephalic
and have congenital heart
disease due to the maternal
levels of phenylalanine, which
cross the placenta
Thats why its
important for females
of childbearing age to
continue with their
dietary restriction
Treatment: dietary restriction of phenylalanine
Epidemiology:
Affects 1 in 10,000 Caucasian infants
Common in persons of Scandinavian descent;
uncommon in African Americans and Jewish
populations
o Benign hyperphenylalaninemia
Mutation of PAH gene that results in modest elevation of
blood phenylalanine levels BUT NO NEUROLOGIC
DAMAGE
Infants will still test positive for PKU, but do not require
dietary restrictions
Need to perform serum phenylalanine levels to
differentiate between benign
hyperphenylalaninemia and PKU
o Variant forms of PKU
Caused by abnormalities in the synthesis or recycling of the
cofactor tetrahydrobiopterin (BH4)
These pts cannot be treated by dietary restrictions
Galactosemia
o Pattern of inheritance: autosomal recessive
Heterozygotes have mild enzyme deficiency but do not
have the clinical and pathologic consequences seen with
homozygotes
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o Mechanism:
Common variant: galactose-1-phosphate uridyl transferase
deficiency
Rare variant: galactokinase deficiency
o Result:
Buildup of galactose-1-phosphate in tissues, which is used
by alternative metabolic pathways to create toxic
intermediates such as galactitol and galactonate
o Clinical features:
Hepatomegaly due to fatty change and jaundice occurs
within the first week of life
Resembles cirrhosis of alcohol abuse
Cataracts/opacification of the lens
Galactitol in the eye causes the lens to absorb
water and swell and increase osmotic pressure
Occurs within first few weeks of life
Nonspecific alterations in the CNS
Loss of nerve cells, gliosis, edema in the dentate
nuclei of the cerebellum and olivary nuclei of the
medulla
Mental retardation can occur within the first 6 to 12
months of life
Infants fail to thrive from birth
Vomiting and diarrhea within a few days of milk ingestion
Kidneys
Build up of galactose-1-phosphate impairs amino
acid transport aminoaciduria
E. coli Septicemia due to a decrease in PMN bactericidal
activity
Hemolysis and coagulopathy
o Treatment
Early removal of galactose from diet for at least first 2 years
of life
Can allow for almost normal development and
prevent lots of the symptoms
Some older patients, even following dietary restrictions, are
affected by speech disorder, gonadal failure, and ataxia
Rizwan 466-471
Cystic Fibrosis (Mucoviscidosis)
Cystic fibrosis = inherited disorder of ion transport that affects fluid secretion
in exocrine glands and in epithelium of RESPIRATORY, GI, and
REPRODUCTIVE tracts
Clinical features = chronic lung disease secondary to recurrent
infections, pancreatic insufficiency, steatorrhea, malnutrition, hepatic
cirrhosis, intestinal obstruction, male infertility
CF is MOST COMMON lethal genetic DISEASE for CAUCASIANS (1 in
2500)
AUTOSOMAL RECESSIVE but heterozygotes have higher incidence of
Respiratory and Pancreatic disease not completely mendelian b/c CF pts
can have a lot of mutations
Morphology
SWEAT GLANDS morphologically UNAFFECTED in all variants
PANCREATIC DUCT ABNORMALITIES present 90% of CF cases
o Milder cases the exocrine glands only have small accumulations
o Severe cases have full plugging causing atrophy and stops fat absorption and accompanying
Avitaminosis A causes squamous metaplasia of ducts
o Mucus plugs in small intestine of infants cause small-bowel obstruction known as MECONIUM
ILEUS
LIVER involvement causes STEATOSIS and eventually plugs up bale canaliculi causing FOCAL BILIARY
CIRRHOSIS
SALIVARY GLAND ATROPHY, fibrosis, and squamous metaplasia
PULMONARY problems including hyperplasia and hypertrophy of mucus secreting cells causing
secondary infections and lung abscess which is most serious
o S. AUREUS, H. INFLUENZAE, PSUEDOMONAS AERUGINOSA, Non-TB mycobacteria,
allergic bronchopulmonary aspergillosis, and the BURKHOLDERIA CEPACIA complex (of which
B. CENOCEPACIA is most common in CF and leads to cepacia syndrome of fulminant illness,
mortality)
AZOOSPERMIA and INFERTILITY b/c Congenital absence of both vas deferens in 95% of male patients
Clinical Features
10 - Diseases of Infancy + Childhood
10% of cases present at birth thru MECONIUM ILEUS or later as RLQ pain
90% of all cases have EXOCRINE PANCREATIC INSUFFICIENCY
associated w/ 2 severe mutations or 1 severe + 1 mild BUT not 2 mild
mutations (they are called pancreas-sufficient phenotype)
o Pancreatic insufficiency => protein/fat malabsorption and
increased fecal loss => fat soluble avitaminosis of A, D, K +
hypoproteinemia causing edema + persistent diarrhea
o Pancreas-sufficient pts has normal growth/development but have
recurrent pancreatitis and other features of classic CF
Nonclassic/Atypical Cystic Fibrosis: usually have 1 mild + 1 severe
mutation leading to absence of classical features of CF but they do have
idiopathic chronic pancreatitis
o Random fact: Endocrine Pancreatic Insufficiency aka Diabetes is
uncommon in CF
CARDIORESPIRATORY COMPLICATIONS
o Cor pulmonale, persistent lung infections with 80% P.
AERUGINOSA, and 3% B. CEPACIA some are even resistant
strains
o RECURRENT SINONASAL POLYPS in of cases
o Nonclassic or Atypical CF present with adult-onset IDIOPATHIC
BRONCHIECTASIS
LIVER DISEASE
o Liver disease onset is puberty and can lead to death
o Asymptomatic hepatomegaly present in 1/3 of cases
o Common bile duct obstruction can cause jaundice and diffuse
biliary cirrhosis happens in 10% of CF pts
AZOOSPERMIA/INFERTILITY
o Bilateral congenital absence of vas deferens
Most patients are brought in because of salty sweat but not every CF pt has
salty sweat
Gold standard for CF diagnosis: sequencing of CFTR gene
Symptoms for Diagnosis
o Sequencing for CFTR gene = GOLD STANDARD
o Elevated sweat electrolytes (salty sweat)
o Sinopulmonary disease
o Gastrointestinal manifestations
o Nasal transepithelial potential difference
o Family history
Management of CF
o Antimicrobial therapy
o Pancreatic enzyme replacement
o Bilateral lung transplantation
o CFTR "potentiator"
For CF patients with G155D mutation in CFTR gene
Take potentiator orally to restore ion transport function in
defective channel
o Life expectancy now ~ 40 years
Tasfia 471-475
Incidence + types
o Most frequent childhood cancer occur in:
Hematopoietic system
Nervous tissue
Soft tissue
Bone
Kidney
o Most frequent adult cancer occur in
Skin
Lung
Breast
Prostate
Colon
o Neoplasms with high incidence in children < 10 yrs old
Leukemia (especially acute lymphoblastic leukemia)
Neuroblastoma
Wilms tumor
Hepatoblastoma
Retinoblastoma
10 - Diseases of Infancy + Childhood
Rhabdomyosarcoma
Teratoma
Ewing sarcoma
Posterior fossa neoplasms
Juvenile astrocytoma
Medullablastoma
Ependymoma
o Leukemia results in most deaths under age 15
o Histology
Malignant non-hematopoietic pediatric neoplasms
Undifferentiated
Sheets of cells
Small round nuclei
Organogenesis specific to site of tumor origin
o Reason for name "blastoma"
Called "Small round blue cell tumors"
o Because of primitive appearance
Two types of malignant tumors discussed below:
Neuroblastoma
Wilms Tumor
Louis 476-481
Neuroblastoma
Tumor of adrenal medulla + sympathetic chain, derived from primordial neural
crest cells
Most common extracranial solid tumor of childhood
Mutation in anaplastic lymphoma kinase (ALK) gene; tx w/ small molecular
inhibitors
Morphology
o Range from in situ lesions (minute nodules) to large masses
o In situ lesions often spontaneously regress
o Histologically
primitive-appearing cells w/ dark nuclei
Background neuropil (fibrillary material) representing
neuritic processes; neuropil = any area in nervous system
composed of unmyelinated axons (eg brain)
Homer-Wright rosettes = tumor cells surround neuropil
Ganglioneuroblastoma = ganglion cells mixed w/
neuroblasts
Ganglioneuroma = mature ganglion cells w/ few
neuroblasts
Schwann cells - req for designation of above 2 ganglio-
tumors, and is assoc w/ favorable outcome
o INSS Staging Criteria
1 Localized tumor w/ gross excision
Ipsilat LN - for tumor