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Block V, Week V


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susceptibility of a fetus to teratogens depends on what three factors?
1. genotype
2. # of interactions with teratogen
3. developmental stage of fetus
Describe the susceptibility of teratogens during the following fetal times:
1. 0-14 days (preimplantation and implantation)
2. 15-60 days (early and late organogenesis)
3. 60-280 days (fetal period)
1. resistant time for embryo: all or nothing response
3. not as susceptible
1. dysraphic anomalies
2. atresia
1. defects caused by the failure of apposed structures to fuse
2. defects caused by incomplete formation of a lumen.
what are two possible results of defects in either cell proliferation or induction?
1. death
2. agenesis
a defect in cell differentiation would result in? (2)
Hamartomata (tumor growth)
what are three possible results of a defect in migration?
1. non-fusion
2. fusion
3. misplacement
during embryonic development, a defect in cell death would result in?
persisting transitory structures
a theory postulating how FAS develops involves inhibition of retinol dehydrogenase, thereby resulting in a lack of product.
What is the product and why is this product important?
retinoic acid
important in homeostasis and normal fetal tissue development.
what is a physical sign seen in newborns that almost always indicates intracranial pathology?
What does TORCH stand for?
Herpes simplex
what is the diagnostic tool for CMV in an infant?
intranuclear inclusion bodies in urine sediment.
what are some common effects seen in a newborn that is infected with a TORCH agent?
Microcephaly, focal cerebral calcifications
Cataracts, chorioretinitis
heart disease
purpura and petechiae
a pregnant woman that has ingested Thalidomide has (in general) a ___% risk of having a child with birth defects?
What is the timeperiod in the pregnancy that thalidomide is a teratogen?
21-33 days post conception
what are the hallmark clinical manifestations of a thalidomide baby?
microtia or anotia
phocomelia or amelia (flipper or no arms)
cardiac defects
describe the mental status of a child with:
1. FAS
2. CMV
3. Thalidomide exposure
1. MR, learning disabilities, ADHD
2. MR
3. Normal intelligence
4p- syndrome is also known as?
Wolff-Hirschkoff syndrome
Hallmark phenotype of a child with 4p- syndrome?
growth retardation
"Grecian Helmet" facies
hypertelorism, cleft lip or palate
Which disorder is characterized by a clenched fist with overlapping digits (2nd over 3rd, 5th over 4th)?
Trisomy 18
what is another hallmark phenotype of a child with trisomy 18?

rocker-bottom feet
(also short sternum, cardiac defects)
which disorder is characterized by midline facial defects?
trisomy 13
what is another hallmark phenotype of a child with trisomy 13?

(hyperconvex nails, microcephaly)
compare the mortality rates of trisomy 13 and 18.
trisomy 13 - 50% mortality first month
trisomy 18 - 95% mortality first year
most of these fetuses (66-75%) are lost during pregnancy
what is the genotype of an individual with Klinefelter Syndrome?
Describe the morphology and function of the testes in an individual with Klinefelters
Seminiferous tubules: atrophy, hyalinization, fibrosis
Germ Cells and Sertoli Cells: absent
Leydig cells: increased in number, function impaired
what would the following hormone levels be in an individual with klinefelters?
1. Testosterone
2. Estradiol
3. LH, FSH
1. Low
2. High
3. High
hallmarks in the phenotype of a Klinefelter individual?
tall, eunochoidal
phenotypic male genitalia
female escucheon
mental status of a klinefelter individual?
reduced IQ
behavioral and personality problems
what is the genotype of an individual with Turner Syndrome?
(3/4 of X's maternal origin)
clinical features of Turner?

short stature
web neck
coarctation of aorta, bicuspid aortic valve
rudimentary ovaries
multiple nevi
mental status of an individual with Turner's?
normal IQ
some learning disablities (esp. math, visual-spacial)
Wardenburg's syndrome is caused by a failure of normal neural crest cells to migrate and differentiate. What are three cell lines derived from neural crest cells that are affected?
1. Melanocytes
2. Colonic Ganglion Cells
3. Hair cells in Organ of Corti
what is the inheritance of Wardenburg Type I syndrome?
autosomal dominant
Clinical features of Wardenburg Type I?
white streak in hair
unilateral/bilateral deafness
hypopigmented ocular fundus
Hirschprung's disease (colonic aganglionosis)
Dandy-Walker malformation is a type of?
the genetic inheritance of hydrocephalus is varied:
1. genetic defect specifically resulting in atresia of the foramina of Luschka and Magendie?
2. what about Congenital Sylvius aqueductal stenosis?
1. autosomal recessive
2. X-linked recessive
Clinical hallmarks of hydrocephalus?
Large tense fontanelle, ventricular enlargement
"sunsetting" of pupils"
sixth nerve palsy: limitation of upward gaze
hyperactive deep tendon reflexes
what is the theorized pathogenesis of hydrancephaly?
early fetal obstruction of carotid vessels: results in no cerebral tissue. Brainstem still present b/c basilar arteries are not blocked.
clinical manifestations of hydrancephaly?
enlarged head, large fontanelle
preservation of MORO reflex, rooting and sucking
treatment for hydrancephaly?
(still observe progressive deterioration, most deaths due to pneumonia)
what type of genetic disorder is myotonic dystrophy (MD)
autosomal dominant
trinucleotide repeat expansion
which enzyme is defective in MD?
myotonia protien kinase
how does "characteristic myotonia" manifest in an EMG?
"dive bomber" sound
Clinical hallmarks of myotonic dystrophy?
myotonia w/sustained grip (handshake that is slow to relax)
facial weakness, inability to bury eyelashes
ptosis, cataracts
what is the inheritance of congenital myotonic dystrophy?
autosomal dominant
clinical manifestations of congenital myotonic dystrophy?
severe hypotonia
facial weakness
poor feeding
respiratory insufficiency
what type of mutation is observed in spinal muscular atrophy and what structure is affected by this mutation?
deletion mutation
Reduction in survival motor neuron (SMN) protien
what would you expect the motor nerve conduction to be in SMA?
What would you expect the EMG results to be?
(EMG shows denervation)
clinical hallmarks of SMA I?
no reflexes
respiratory problems, diaphragmatic breathing
cannot sit alone
what is a major clinical difference between SMA I and SMA II?
SMA I - earlier onset, child cannot sit
SMA II - later onset, child can sit
compare the age of death in SMA I, II and III.
SMA I - less than 2 yrs
SMA II- greater than 2 yrs
SMA III- adult
Compare the muscle biopsies of SMA I, II and III.
SMA I and II similar, see clusters of large fibers
SMA III - more normal
clinical manifestations of SMA III?
can walk with braces
proximal weakness, utilize Gower maneuver
what are the distinguishing features between spinal muscular atrophy (SMA) and muscular dystrophy?
muscular dystrophy patients have large calves;
SMA pts. do not
both utilize Gower maneuver
what is the disorder?
- impaired rod/cone function
- can be autosomal dominant, recessive or X-linked recessive
retinitis pigmentosa
clinical manifestations of retinitis pigmentosa?
tunnel vision
decreased dim light vision
diffuse retinal depigmentation
affected color vision
what is the avg. time of onset for retinitis pigmentosa?
1st-2nd decade
(result is severe vision loss 4th-7th decade)
Appearance of Lisch nodules is characteristic of?
Neurofibromatosis I
what is the genetic defect in neurofibromatosis I?
defect in NFI gene
pathophysiology of neurofibromatosis?
neurofibromin protien normally inactivates Ras: when neurofibromin is defective Ras activity is uncontrolled and neurofibromas form
what other clinical manifestations are present in neurofibromatosis I?
cafe-au-lait spots
skeletal lesions
(lisch nodules, neurofibromas)
what is a plexiform neurofibroma (vs. a regular neurofibroma)?
plexiform neurofibromas are cutaneous and raised, neurofibromas are not
which disease is known for its characteristic "candle drippings"? (subependymal nodules)
where are these found?
Tuberous Sclerosis Complex (TSC)
candle drippings are found on ventricular walls
which genes are mutated in TSC?
what do these genes encode?
both encode tumor supressor proteins
what is the inheritance of TSC?
autosomal dominant
pathophysiology of TSC?
disordered or arrested migration of neuroectoderm
Clinical manifestations of TSC?

facial angiofibromas "adenoma sebaceum"
cardiac rhabdomyomas
kidney angiomyolipomas
ash leaf spots
which disorder is characterized by a port wine stain along the trigeminal nerve?
Sturge Weber
what is the primary problem in Sturge Weber disorder?
vascular plexus abnormality
Other clinical manifestations of Sturge-Weber?
intracranial hemangioma, calcification
which disorder is characterized by abnormal vesicles in the epidermal layer secondary to recurrent minor trauma?
Epidermolysis Bullosa Simplex
inheritance pattern of EB?
abnormal protien?
autosomal dominant
abnormal keratin
what is the progression of EB immediately following a minor trauma?
cytoplasmic vacuoles
rupture of plasma membrane leading to cell lysis
intraepidermal vesicles
healing w/o atrophy or scarring
ichthyosis vulgaris is a disorder resulting in defects of which two molecules?
Which disorder am I?
rocker bottom feet
trisomy 18
Which disorder am I?
purpura and petechia
(specifically CMV)
Which disorder am I?
Candle drippings (subependymal nodules)
Tuberous Sclerosis Complex (TSC)
Which disorder am I?
port wine stain?
Struge Weber
Which disorder am I?
Dandy-Walker malformation
Which disorder am I?
Grecian Helmet facies
Which disorder am I?
cafe-au-lait spots
Which disorder am I?
tunnel vision, decreased light vision, abnormal ocular pigmentation
retinitis pigmentosa
Which disorder am I?
Gower maneuver
spinal muscular atrophy III
muscular dystrophy
Which disorder am I?
white forelock
Waardenburg Type I
Which disorder am I?
47 XXY
Klinefelter Syndrome
Which disorder am I?
midline facial defects
trisomy 13
Which disorder am I?
"basically anencephaly with the skull closed"
Difference between malformation and deformation?
malformation - caused by abnormal development
deformation - caused by mechanical forces
What is the name of the disease that is due to abnormal zinc absorption?
Acrodermatitis Enteropathica
what is the precise reason why there is abnormal zinc absorption in an individual with acrodermatitis enteropathica?
there is an absence of low molecular weight zinc binding factor
In an individual with acrodermatitis enteropathica, what would you expect the serum zinc levels to be?
what are some hallmark symptoms seen in acrodermatitis enteropathica?
- vesiculopustular erruptions (mouth, anus, genitals, distant extremities)
- alopecia
- severe diarrhea
- abnormal humoral/cellular immunity
- lethargy
is there a treatment for acrodermatitis enteropathica?
administer oral Zinc
which disorder is a result of a missense mutation in the fibrillin-1 gene?
Marfan syndrome
what are some skeletal manifestations of Marfan syndrome?
- tall stature
- arachnodactyly
- joint hypermobility
- pectus excavatum or carinatum
- walker-murdoch wrist sign
- steinburg thumb sign
what is the occular hallmark that suggests Marfan syndrome?
upward lens subluxation
describe the cardiac mainifestations of marfan syndrome
aortic dilitation, regurgitation, often results in aneurism of aortic root
which disorder is characterized by deficient or defective collagen?
describe the heredity of the different types of ED
ED I, II and III - AD
ED IV - can be AD or AR
which types of ED are known as classical ED and what exact defect is present?
types I and II
defect in type V collagen
describe the clinical manifestations of ED I
- joint hypermobility
- skin hyperextensibility
- increased skin fragility (cigarrete paper like scarring)
- generalized tissue fragility, difficulty with wound healing
describe ED II in relation to ED I
ED II is milder than ED I
- joint hypermobility is confined to hands and feet
- minimal cutaneous involvement
- tissue fragility rarely a problem
What is the one clinical distinction seen in ED-III?
SEVERE hypermobility of all joints, usually without muscle or skeletal deformity
ED-IV is described as mainly what type of symptoms?
what are some clinical manifestations of ED-IV?
- spontaneous rupture of arteries
- spontanous perforation of bowel
- prominent veins, easily bruise
"gaunt, esthetic look"
which type of ED is the most severe?
(Potentially lethal)
which disease is often mistaken for child abuse by clinicians?
osteogenesis imperfecta I
what is synthesized less in OI type I?
less type I procollagen
(therefore less type I collagen)
describe the collagen "population" in bone matrix in a patient with OI-I
- reduced type I collagen
- relatively increased type III collagen
(therefore increased type III/type I collagen ratio)
what are some clinical manifestations of OI-I?

- multiple fractures before the age of 5 yrs. (decreased bone fragility after puberty)
- blue sclera
- bowed extremities
- osteopenia
- otosclerosis/conductive hearing abnormalities
what is the mutation type in OI-II and what gene is the mutation in?
point mutation in type I collagen gene (COL 1 A1 or COL 1 A2)
compare OI-II to OI-I
OI type II is more severe, can be lethal
OI type I individuals can live into adulthood
what are some clinical manifestation of OI-II?

- multiple in-utero fractures
- crumpled humerus and femurs
- limb avulsion during delivery
- blue sclera
- wormian bones
what is the life expectancy of an individual with OI-II?
die as a young infant
which disorder is often mistaken for osteogenesis imperfecta and has "telephone-receiver" bones?

thanatophoric dysplasia I
Describe the X-ray differences between OI and thanatophoric dysplasia I
- accordian-type bones (rippled, wider)
- multiple rib fractures

thanatophoric dysplasia:
- telephone receiver bones
- narrow chest
- no rib fractures
what is the mutation in thantophoric dysplasia I?
what does this mutation result in?
mutation in FGF 3 receptor.
this results in NEGATIVE bone growth activation
describe the major abnormalities seen in an infant with thanatophoric dysplasia I

- impaired endochondral ossification, growth plate disruption
- macrocephaly
- marked shortage of extremities
- brain abnormalities
what is the life expectancy of an infant with thanatophoric dysplasia I?
death shortly after birth
what is the hereditary pattern of most metabolic disorders?
a patient with a deficiency of cystathione beta synthase has what metabolic disorder?
what disorder is homocystinuria similar to and how can they be differentiated? (3 clinical symptoms)
similar to Marfan's syndrome
- homocystinuria has mental retardation, Marfan's does not
- homocystinuria has downward lens dislocation, marfan's has upwards.
- homocystinuria has thromboembolic events, marfan's does not
what would the urinary and plasma tests show in an individual with homocystinuria?
urine - elevated homocystine
plasma - increased methionine, decreased cystine
what eye manifestations would you see in homocystinuria?
downward lens dislocation
which metabolic disorder is characterized by a deficiency in glucocerebrosidase (beta-glucosidase)?

Gaucher disease
what is a Gaucher cell?
(where are they found, what is in them)

lipid-laden macrophages found in spleen, liver, bone marrow and lymph
- glucosylceramide accumulates in the lysosomes
what are the three types of Gaucher disease and what is each type characterized by?
type 1. (chronic non neuropathic)
type 2. (acute neuropathic)
type 3. (subacute neuropathic)
types 2 and 3 are rare
where is Gaucher disease type I most commonly found?
among the Ashkenazi Jews
clinical manifestations of Gaucher disease?

- hepatosplenomagaly
- anemia, bleeding tendancy, fatigue
- thrombocytopenia
- skeletal fractures (erlenmeyer flask fractures)
which disorder is characterized by a deficiency of hypoxanthine-guanine-phosphoribosyl transferase (HGPRT)?
Lesch-Nyhan Syndrome
Lesch-Nyhan syndrome leads to an accumulation of what (2), which leads to an accumulation of what (1)?
an accumulation of hypoxanthine and guanine
leads to an accumulation of uric acid
what are some clinical manifestations of Lesch-Nyhan syndrome?

- self mutilation (prefer to be in restraints)
- mental retardation
- gouty arthritis
- tophi: uric acid deposits (seen on pinna)
- obstructive nephropathy
which metabolic discorder is characterized by copper malabsorption?
Menke syndrome
what are some clinical manifestations of Menke syndrome?
- hair abnormalities
- cortical neuron loss
- cerebellar dysfunction
- "cherubic" face
- seizures
- tortuous cerebral vessels
what is the prognosis for an individual with Menke syndrome?
progressively fatal, no cure known as of yet
in an individual with Menke syndrome, what would you expect the serum copper and ceruloplasmin levels to be?
what would you expect the erythrocyte copper levels to be?
serum and ceruloplasmin levels will be low
erythrocyte levels will be normal
what would calcium and phosphorous levels be in a patient with albright hereditary osteodystrophy?
calcium - low
phosphorous - high
what leads to the abnormal Ca++ absorption seen in albright hereditary osteodystrophy?
a mutation in a G protein leads to an impairment of the cAMP response to parathyroid hormone. No response to PTH results in no Ca++ absorption
what other hormones are coupled to cAMP and are therefore impacted by albright hereditary osteodystrophy?
which sex in albright hereditary osteodystrophy most often seen in?
which sex is it more severe in?
most often seen and most severe in females (females affected 2-1 compared to males)
describe the IQ of an individual w/ albright hereditary osteodystrophy.
LOW (20-99 with a median of 60)
what are some other clinical manifestations of albright hereditary osteodystrophy?

- obesity, rounded face
- delayed dentition
- shortened metacarpals and metatarsals (4th and 5th)
- diabetes mellitus and insipidus
- short stature
which disorder is a result of an 11p duplication and presents as hypoglycemia?

what would an infant look like that was born with Beckwith-wiedemann?
Large (somatic gigantism)
- due to increased insulin, growth hormone and insulin like factor
what are some clinical manifestations of beckwith-wiedemann?

- macroglossia
- omphalocele
- ear lobe linear fissures
if beckwith-wiedemann is not detected in the nursery what could occur?
nephroblastoma or adrenocortical carcinoma
(secondary to hemihypertrophy)
which disorder is a result of a 5-alpha-reductase deficiency or a cytosol receptor defeiciency? (secondary to a genetic defect)
Testicular feminization (androgen insensitivity syndrome)
what is the inheritance of testicular feminization?
Which reproductive organs are present in testicular feminization?

testes present
uterus absent
normal external female genitalia
individuals with testicular feminization are phenotypically ___, gonadally ____, chromosomally ____ and overall are considered ____.
phenotypically female
gonadally male
chromosomally male
overall considered female
a buccal smear taken of an individual with testicular feminization will come back as which sex?
what are some clinical manifestations of testicular feminization?

- infertility, amenorrhea
- sparse to absent pubic or axillary hair (due to no testosterone response)
- breast development
- shortened vagina
A midline caudal defect that affects multiple systems, presents as potter facies, fused lower extremity and most often stillborn is?
sirenomelia sequence
describe the clinical manifestations of the sirenomelia sequence
- fused lower extremity
- absent genitalia, bladder, anus
- potter facies
- lung hypoplasia
- TE fistula
what is "Potter syndrome," also known as the oligohydramnios tetrad

1. oligohydramnios
2. Potter facies (due to compression of face)
3. Pulmonary hypoplasia
4. Renal agenesis
the following trait is often seen in the following disorders:
trisomy 13
trisomy 18
describe the clinical manifestations and associations of cyclopia
- fusion of optic vesicles
- agenesis of corpus collosum
- absence of olfactory tract
- absent midline structures
- cleft lip/palate
What is the life expectancy of an individual with cyclopia?
most are stillborn
can survive up to 10 yrs
what is the name of the disorder characterized by an aged "dwarflike" appearance and lax, wrinkled skin?
gerodermia osteodysplastica
what is the inheritance of gerodermia osteodysplastica?
what are some other clinical manifestations of gerodermia osteodysplastica?
- lax, wrinkled skin
- aged appearance
- osteoporosis
- joint laxity
- fractures
- ptosis
what is the life expectancy and intelligence of an individual with gerodermia osteodysplastica?
normal life expectancy, normal intelligence
what is the disorder characterized by excessive hair and abnormal teeth? (akin to "werewolf"...)

hypertrichosis lanuginosa universalis
what is the most common type of dwarfism?
what are the two main defects in achondroplasia and what is the inheritance of achondroplasia?
1. mitochondrial oxidative system defect
2. FGF 3 receptor defect
autosomal dominant with complete penetrance
what are some complications seen in achondroplasia?

spinal cord compression
obstructive sleep apnia
what, skeletally, is wrong in achondroplasia

- broad and disorganized epiphyseal growth plate
- large cartilagenous epiphysis as compared to short diaphysis
these three drugs, if taken by the mother, can result in?
Valproic acid
conjoined twins
what is the genetic problem in Angelmann syndrome?

15 (q11-13) deletion
genomic imprinting is seen here
what are some clinical manifestations of Prader-Willi?

- hypotonia
- obesity (decreased perception of satiety)
- hypothermia, hypogonadism
- small hands and feet
- delayed psychomotor development
Which 2 disorders show a paternal age effect?
1. Marfan syndrome
2. Achondroplasia
which disorder displays "Wormian" bones
osteogenesis imperfecta I and II
which disorder displays telephone reciever bones?
Thanatophoric dysplasia I
which disorder displays erlenmeyer flask fractures?
Gaucher disease
which disorder has a high risk of aortic aneurisms and therefore we prohibit acceleration/deceleration sports for these patients?
Marfan syndrome

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