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74 Cards in this Set
- Front
- Back
Autosomal Dominant
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Vertical transmission of the disease phenotype, lack of skipped generations, and roughly equal numbers of affected males and females.
Recurrence risk is 50%. Example: Postaxial polydactyly |
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Autosomal Recessive
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Clustering of the disease phenotype among siblings, but not usually seen among parents or other ancestors. Equal numbers of affected males and females. Consanquinity may be presents.
Relative risk is 25% Example: Albunism |
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Incomplete (Reduced) Penetrance
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A person who has the disease-causing genotype might not exhibit the disease phenotype at all, even thought the disease-causing mutation can be trasmitted.
Example: Retinalblastoma - 10% of obligate carriers of the retinoblastoma-causing mutation (affected parent and affective children) do not have the disease. |
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Variable Expression
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Degree of severity of the disease phenotype.
Maybe caused by environmental effects, modifier loci, or allelic heterogenity. Example: Neurofibromatosis, type 1. |
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Age Dependent Penetrance
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Delay in the onset of a genetic disease.
Example: Huntington Disease |
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30 y/o woman had a sister who died from Tay-Sachs disease, an AR disorder that is fatal by age 6. What is the probability that this woman is a heterozygous carrier of the Tay-Sachs mutation
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2/3 heterzygous carrer
Remember, both parents had to be heterozygous carriers since they both lived past 6 years. She cannot be an affected homozygote because affected individuals die by age six, so either: 1. Disease allele from mother and normal allele from father 2. Disease allele from father and normal allele from mother, or 3. Normal allele from both parents. |
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X-linked Recessive
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Absence of father-to-son transmission, skipped generations when genes are passed through female carriers, and a preponderance of affected males.
Example: Duchenne Muscular Dystrophy, Hemophilia A, Red-Green Colorblindness |
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X-linked Dominant
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Absence of father-to-son transmission, skiiped generations are uncommon, twice as common in females as in males.
Example: Hypophosphatemic Rickets, Rett Syndrome (most males die in utero) |
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Multifactorial Inheritance
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Many traits thought to be influenced by multiple genes as well as environmental factors.
Example: Height, Blood Pressure |
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Mitochondrial Inheritance
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Mitochondria have their own DNA. Mitochondiral DNA is maternally inherited and has a high mutation rate.
Example: Leber Hereditary Optic Neuropathy (LHON) - missense, Myoclonic Epilepsy with ragged-red fibers (MERRF) - single base mutation, Kearns-Sayre disease - deletion/duplication. |
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Prenatal Screening - Invasive
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Analysis of fetal tissue (amniocentesis, chorionic villus sampling, cordocentesis, and preimplantation genetic diagnosis)
- More cards in detail. |
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Prenatal Screening - Noninvasive
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Visualization of the fetus
(Ultrasonography, MRI) - More cards in detail. |
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Amniocentesis
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- Performed at 15-17 weeks gestation.
- Withdrawl of amniotic fluid. - Amniotic AFP is elevated with neural tube defects. - Fetal loss is 1/200 above the background risk level. |
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Indications for Amniocentesis
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- Maternal age > 35.
- Previous child with chromosomal abnormality. - History of structural chromosome abnormality in one parent. - Family history of genetic defect that is diagnosable by biochemical or DNA analysis. - Increased risk of neural tube defect due to positive family history. |
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Chorionic Villus Sampling
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- Performed at 10-11 weeks gestation.
- Provides diagnostic results in more than 99% of cases. - Good for picking up inborn errors of metabolism. - Confirmed placental mosaicism can confuse the diagnosis (mosaicism seen in placenta but not in the fetus - 1% to 2%) - Fetal loss is 1% to 1.5%. |
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Percutaneous Umbilical Blood Sampling (PUBS)
Cordocentesis |
Direct sampling of fetal blood and is used to obtain a sample for rapid cytogenetic or hematological analysis or for confirmation of mosaicism (from CVS).
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Prenatal Screening - Ultrasound
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Used to screen noninvasively for congential defects. Usually done around 18-20 weeks gestation.
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Maternal Serum AFP
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- Considered elevated wen 2 - 2.5 times higher than normal medial level for NTD
- Usually low levels for trisomy 21 and trisomy 18. - Checked at 15-17 weeks post LMP |
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Quadruple screen
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- Unconjugated estriol
- Human chodionic gonadotropin - Inhibin-A - AFP |
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First-trimester screen
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- Useful for trisomy 21 in 80-85% of cases.
- Also trisomy 13 and 18. - free B subunit of hCG - Pregnancy-associated plasma protein A (PAPP-A) - US of nuchal translucency |
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Prenatal Screening - Preimplantation Genetic Diagnosis - Blastomere
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- Checking aneuploidy 3 days after fertilization in vitro.
- DNA amplification for single-gene diseases. - Can lead to allele dropout, where one of the two alleles may be undetectable (heterozygote appears to be a homozygote). |
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Prenatal Screening - Preimplantation Genetic Diagnosis - Blastocyst
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- Done at 100 cell blastocyst stage
- Takes from trophoectoderm of blastocyst, not the embryo. - Avoids allele dropout. |
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Prenatal Screening - Preimplantation Genetic Diagnosis - Polar Body
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- Examination of first or second polar body DNA.
- Useful when only the mother is at risk for transmitting a disease-causing mutation. |
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Karyotype
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Ordered display of choromosomes.
Uses FISH - Useful for detection of balanced translocation in developmental delay as part of an area could be cut of for transcription. (CGH will NOT pick this up). |
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FISH
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Useful for detecting missing or additional chromosomal material and rearrangements.
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array Comparative Genomic Hybridization (aCGH)
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Differentially labeled DNA from test and control subjects is hybridized to metaphase in microarrays, allows the detection of deletions or duplications. Cannot identify balanced rearrangements.
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Newborn Screening
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Blood spot sent for genetic testing of multiple diseases that can cause morbidity and mortality and early diagnosis of chronic diseases.
Examples: PKU, Galactosemia, Congenital Hypothyroidism, CF |
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Trisomy
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Three copies of a chromosome.
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Deletions
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Chromosomal break and subsequent loss of genetic material.
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Translocations
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Interchange of genetic materal between nonhomologous chormosomes.
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Duplications
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Unequal crossover during meiosis.
Less severe than deletions. |
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Inversions
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Two breaks on a chromosome and reinsertions of the intervening fragment in inverted order.
ABCDEFG to ABEDCFG |
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Contiguous Gene Syndromes
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Deletion of a series of adjacent genes
Example: WAGR syndrome (11p deletion). |
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Turner Syndrome
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45 X
Proportionate short stature Triangle-shaped face Posteriorly rotated ears Broad, "webbed neck" Broad chest Obstructive cardiac lesions (Bicuspid valve and Coarctation) |
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Klinefelter Syndrome
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47, XXY
Taller than average (Longer limbs) Small testes Gynecomastia Lower IQ scores |
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47 XYY
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Taller than average
Reduced IQ Higher than average male prison population (thought to be due to increase in behavioral disorders and learning disabilities). |
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47 XXX
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Usually benign
Sterility, mestrual irregularity, or mild mental retardation. |
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Pharmacogenetics
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Study of individual genetic variants that modify human responses to pharmacological agents.
Predict a person's response to drugs and reduce the incidence of drug-related side effects. |
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Trinucleotide Expansion
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Increased number of repeats during meiosis or early fetal development that causes genetic disease.
Example: CAG repeat in Huntingtons |
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Imprinting
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One allele from one parent is active, while the other allele is inactive. The silenced genes are said to be imprinted.
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Trisomy 21 - Incidence
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1/800 births
94% have extra chromosome 21 |
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Trisomy 21 - Presentation
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Hypotonia
Small ears Brachydactyly Up-slanted palpebral fisures Epicanthal folds Single tranverse crease ASD, VSD Duodenal atrsia/Hirschsprung |
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Trisomy 21 - Complications
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Hypothyroidism
Atlantoaxial instability Leukemia (ALL) DM Cataracts |
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Trisomy 18 (Edwards) - Presentation
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Intrauterine growth retardation
High forehead Microcephaly Small face and mouth Short sternum Rocker botton feed Clubfoot/clenched fist Overlapping fingers Structural heart defect |
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Trisomy 13 (Patau) - Presentation
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*Think midline defects
Orofacial cleft Postaxial polydactyly of the limbs Holoprosencephaly Hypoplastic or absent ribs Genital anomalies Heart malformations Abd wall defects Cutis aplasia |
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4p- (Wolf-Hirschhorn Syndrome)
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Most common in girls
'Greek helmet' facies (ocular hypertelorism, prminent glabella, and frontal bossing) Growth deficiency Microcephaly 'Beaked' nose Hypertension Short philtrum Hypotonia Cardiac anomalies Seizures |
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5p- (Cri-Du-Chat Syndrome)
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'Cat's cry' changes in larynx
'Moon face' with telecanthus Down-slanting palpebral fissures Hypotonia Short stature Microcephaly High-arched palate Wide and flat nasal bridge Mental retardation |
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18q- (De Grouchy Syndrome)
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*Atretic or narrowed ear canals
'Frog-like' position with legs flexed, ext rotated in hyperabduction Protuding mandible Everted lower lip |
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Angelman Syndrome - Maternall Derived 15q11-13
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Jerky ataxic movements
Characteristic gait Hypotonia Fair hair Mid-face hypoplasia Prognathism (large chin, mandible) Seizures Inapporpriate bouts of laughter Severe mental retardation Absent or severly delayed speech |
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Prader-Willi Syndrome - Paternally Derived 15q11-13
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Severe hypotonia at birth
Obesity (after FTT at birth) Short stature Small hands and feet Hypogonadism Usually mild mental retardation |
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7p11.23- (Williams Syndrome)
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Periorbital fullness with downturned, prominent lower lip
Friendly 'cocktail party' personality Stellate pattern of the iris Strabismus Supravalvular aortic stenosis Mental retardation Hypercalcemia |
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11p13- (WAGR Syndrome)
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Wilms tumor
Aniridia Genitourniary anomalies mental Retardation Absence of 2 possible genes - PAX6 - WT1 (Wilms tumor 1) |
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20p12- (Alagille Syndrome)
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AD, Mutation in JAG1 gene
Bile duct paucity with cholestasis Pulmonary valve stenosis and peripheral artery stenosis Ocular defects Skeletal defects - butterfly vertebrae Triangular facies, pointed chin Long nose with broad mid-nose |
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22q11.2- (DiGeorge Syndrome)
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Cleft palate, velopharyngeal incomppetence (VPI)
Thymus agenesis or hypoplasia (immune deficiencies) Parathyroid gland hypoplasia/agenesis (hypocalcemia) Hypoplasia of the auricle and external auditory canal Cardiac abnormalities (TOF>Aortic arch>VSD>TA) Short stature Behavioral problems Defect of development of third and fourth phayngeal pouches |
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Klinefelters Syndrome
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47, XXY
Tall with gynocomasita Delayed 2nd sex development Azoospermia, small testes |
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Turners Syndrome
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45, X
Short stature Ovarian failure/gonadal dysgenesis Cardiac (Bicuspid aortic valve>coarctation) Broad webbed neck Posteriorly rotated ears Lymphedema of the hands and feet Cubitus valgus |
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Cleft lip and/or cleft palate
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Sporatic, familial and herediatry causes
Fix lip within first 5 months Fix palate 6-12 months |
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Pierre-Robin Sequence
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Primary embryologic defect of mandibular hypoplasia
Displacement of tongue Interrupted closure of the lateral palatine ridges Cleft palate Glossoptosis Micrognathia Respiratory distress Feeding problems |
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Amniotic Band Sequence
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Amniotic bands adhereing to any part of the fetal body
Disruptive clefts of face and palate Constriction risngs of the limbs and/or digits Amputations |
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Hemifacial Microsomia
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Microtia/Anotia
Canal atresia Perauricular tags Cervical vertebral anomalies Cardiac anomalies Renal anomalies |
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Goldenhar Syndrome
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Same as Hemifacial Microsomia + Epibulbar Dermoids
Microtia/Anotia Canal atresia Perauricular tags Cervical vertebral anomalies Cardiac anomalies Renal anomalies |
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Branchio-Oto-Renal Syndrome
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AD
Branchial cleft istulas/cysts Perauricular pits Cochlear/Stapes malformation Mixed sensory and conductive hearing loss Renal dysplasia Pulm hypoplasia - rare |
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Treacher-Collins Syndrome
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AD
Mandibular/Maxillary hypoplasia Zygomatic arch clefts |
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Achondroplasia
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AD with FGFR3 (most are de novo, increases with advancing PATERNAL age)
Disproportionately short stature with rhizomelic shortening Trident hands Macrocephaly Flat nasa bridge, prominent forehead, and midfacial hypoplasia |
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Achondroplasia - Complications
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Serous otitis media
Motor milestone delay Bowing of legs Foramen magnum stenosis and/or craniocervical junction abnormalities during infancy - compression of upper cord causing apnea, quariparesis, growth delay, and hydrocephalus. |
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Thanatophoric Dysplasia
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Type I - bowed femurs
Type II - straight femurs, 'cloverleaf' skull AD - FGFR3 (most are de novo) Most are lethal Macrocephaly with short limbs Xray shows platyspondyly (flatness of bodies of vertebrae) flared metaphyses and short iliac bones |
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Osteogenesis Imperfecta - General
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Osseous fragility
Short stature Skeletal findings of variability *None cause retinal hemorrhage or subdural hematomas - Think NAT |
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Osteogenesis Imperfecta - Type I
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Mildest and most common form
Blue sclera Delayed fontanelle closure Hyperextensible joints Hearing loss Stature near normal Multiple fractures (most occur prior to puberty) *Fractures rarely occur at birth* Scoliosis and hearing loss by age 20-30 |
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Osteogenesis Imperfecta - Type II
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Most severe form
Death in newborn period due to respiratory insufficiency Numerous fractures and severe bone deformity De novo AD mutation of COLIA1 |
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Osteogenesis Imperfecta - Type III
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Point mutation COLIA1
Numerous fractures in newborn Short stature Blue sclera at birth which lighten over time Hydrocephalus and basilar skull invagination (complications) |
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Osteogenesis Imperfecta - Type IV
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Point mutation in COLIA2
(Like Type I) Sclerae white Fontanelle closure delay *Tibial bowing* |
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Marfan Syndrome - General
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AD
Affects eyes, circulatory, skeleton, skin, lung and dura Deaths due to Aortic Root dilation and rupture *Look for 'high arched palate, dislocated lens, pectus carinatum/excavatum, and mitral valve prolapse' |
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Marfan Syndrome - Diagnosis (2010 Ghent Criteria)
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WITHOUT Family History
1. AO and EL 2. AO and FBN1 gene 3. AO and systemic score 7 or higher 4. EL and FBN1 gene with known AO AO = aortic diameter Z score 2 or more EL = Ectopia Lentis WITH family history 5. EL and FH 6. Systemic score 7 or more and FH 7. AO and FH FH = Family History |
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Ehlers-Danlos Syndrome
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AD connective tissue disorders
Hyperextensible skin Hypermobile joints Easy bruising Dystrophic scarring Skin - extra, fragile, abnormal scarring, wrinkled palms and soles Cardiac - MVP and Proximal aortic dilatation |