Block V, Week V
Terms
undefined, object
copy deck
- 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
2. MOST SUSCEPTIBLE TIME for fetus
3. not as susceptible -
define:
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)
-
Agenesis
OR
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?
- fisting
- What does TORCH stand for?
-
Toxiplasmosis
Others
Rubella
Cytomegalovirus
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
hepatosplenomagaly
heart disease
purpura and petechiae - a pregnant woman that has ingested Thalidomide has (in general) a ___% risk of having a child with birth defects?
- 20%
- 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
(nondisjunction) - 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?
-
omphalocele
(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?
- 47,XXY
- 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?
-
gynecomastia
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?
-
45,X
(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?
- hydrocephalus
-
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?
-
transillumination
enlarged head, large fontanelle
preservation of MORO reflex, rooting and sucking - treatment for hydrancephaly?
-
shunt
(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
floppiness
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? -
normal
(EMG shows denervation) - clinical hallmarks of SMA I?
-
hypotonia
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
weakness - 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? -
TSC 1 OR TSC 2
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
MR - 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
coalescence
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?
-
profilaggrin
filaggrin -
Which disorder am I?
rocker bottom feet - trisomy 18
-
Which disorder am I?
purpura and petechia -
TORCH
(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 - Hydrocephalus
-
Which disorder am I?
Grecian Helmet facies -
4p-
(Wolff-Hirschkoff) -
Which disorder am I?
cafe-au-lait spots - neurofibromatosis
-
Which disorder am I?
tunnel vision, decreased light vision, abnormal ocular pigmentation - retinitis pigmentosa
-
Which disorder am I?
Gower maneuver -
spinal muscular atrophy III
OR
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" - hydranencephaly
- 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?
- low
- 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?
- Ehlers-Danlos
- 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?
- vascular
- 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?
-
ED-IV
(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?
-
either:
stillborn
or
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
-
OI:
- 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?
-
stillborn
OR
death shortly after birth - what is the hereditary pattern of most metabolic disorders?
- AR
- a patient with a deficiency of cystathione beta synthase has what metabolic disorder?
- homocystinuria
- 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?
-
TSH
glucagon
FSH
LH -
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?
-
Beckwith-Wiedemann - 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?
- XLR
- 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?
- male
- 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
"mermaidism" - 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:
18p-
trisomy 13
trisomy 18
cytomegalovirus - cyclopia
- 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?
- AR
- 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?
- achondroplasia
- 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
obesity - 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?
Clomaphine
Griseofulvin
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