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Flashcards in Pediatric Syndromes Detailed Deck (52):
1

Name 6 disproportionate dwarfisms

Achondroplasia, MED, SED, DD, Kniest, metaphyseal chondrodysplasia

2

Name 2 proportionate dwarfisms

cleidocranial, mucopolysacc

3

Achondroplasia highlights (10)

- autosomal dominant - FGFR3 - activating mutation proliferative zone physis - spinal stenosis (C and L) - TL kyphosis - rhizomelic - genu varum

4

Apert's (7 features)

- FGFR2

- bilateral complex syndactyly (hands and feet)

- cranial synostosis

- hypertelorism

- radioulnar synostosis

-surgical release of border digits at  ~ 1 year of age

- digit reconstruction ~ 1.5 years of age

5

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Apert

6

SED highlights (6)

- short-trunk dwarfism

- COL2

- congenita (AD and severe)

- tarda (XLR and mild)

- AAI

- short stature, flattened facies, platyspondyly, kyphoscoliosis, coxa vara, genu valgum

7

Conditions with AAI (6)

- Down syndrome

- neurofibromatosis

- Morquio syndrome

- spondyloepiphyseal dysplasia congenita

RA Klippel-veil

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- SED with AAI

9

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SED (platyspondyly )

10

Kniest's Dysplasia features (6)

- disproportionate short-trunk dwarfism

- autosomal dominant, defect leads to abnormal Type II collagen

- retinal detachment and myopia
- otitis media with hearing loss

- joint stiffness / contractures
- dumbell-shaped femora

11

MED features

- irregular, delayed ossification at multiple epiphyses

- short-limbed dwarfism

- Type 1 COMP, Type 2 col9

- valgus knee deformity common

- UPPER CERVICAL INSTABILITY (not AAI)

- short, stunted metacarpals and metatarsals

- may need corrective osteotomy or hemiepiphysiodesis or THA early

 

12

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MED

13

What physeal area is affected in the Metaphyseal Chondrodysplasias (Jansen, Schmid, McKusic)?

- proliferative and hypertrophic zone of the physis (epiphysis is normal)

14

Jansen's 

- autosomal dominant
- defect in parathyroid hormone related peptide (PTHRP)

 

- mental retardation, short limbed dwarfism

- wide eyes, monkey like stance

 

- ostebulbous metaphyseal expansion of long bones seen on xray

15

Schmid's

autosomal dominant
defect in Type X collagen

short limbed dwarfism

excessive lumbar lordosis
trendelenburg gait

diagnosed when patient older due to coxa vara and genu varum, often confused with Ricketts

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16

McKusicks

autosomal reccessive

cartilage hair dysplasia (hair had small diameter)
atlantoaxial instability

ankle deformity due to fibular overgrowth

immunologic deficiency and increased risk for malignancy

seen in Amish population in Finland

17

Cleidocranial Dysplasia

Autosomal dominant

RUNX2/CBFA1 mutation 

absent clavicles, coxa vara,  delay in closure of skull sutures

usually observe most features, may need IT osteotomy for coxa vara

18

Diastrophic Dysplasia

autosomal recessive, mutation in DTDST gene (SLC26A2) on chromosome 5
encodes for sulfate transporter protein, leads to undersulfation of cartilage proteoglycan
progressive deformity

short stature ("twisted dwarf")
cleft palate (60%)
cauliflower ears (80%) = compressive bandage treatment
poorly developed UE
hitchhikers thumb  
thoracolumbar scoliosis**
severe cervical kyphosis**
hip and knee contractures**
genu valgum**
rigid clubfeet (equinocavovarus)**

**needs surgery

19

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diastrophic dysplasia

20

Osteogenesis imperfecta

bones cannot remodel normally
90% have an identifiable genetic mutation, COL 1A1 and COL 1A2 

causes abnormal collagen cross-linking via a glycine substitution in the procollagen molecule

both autosomal dominant and autosomal recessive forms
can be severe or mild (tarda form)

progressive bowing
ligamentous laxity
short stature
scoliosis
codfish vertebrae (compression fx)
basilar invagination
olecranon apophyseal avulsion fx

21

Gaucher Disease

Autosomal recessive deficiency in B-glucocerebrosidase

hematopoetic problems and bone (osteonecrosis, fractures, remodeling problems = metaphyseal dysplasia)

treatment: enzyme substitute Imiglucerase (works well for all but neurologic symptoms) or bone marrow transplant (if early can be curative)

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22

zones of articular cartilage

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23

Superficial (Tangential) Zone Cartilage

- thinnest layer

- highest content of collagen and water...lowest concentration of proteoglycans

-greatest ability to resist shear stresses and serves as a gluiding surface for joint

- limit passage of large molecules between synovial fluid and cartilage (seals cartilage from immune system)

- superficial zone is the first to show changes of osteoarthritis

24

Superficial Zone Cartilage Sub-Layers

 

- fibrilar sheet (lamina splendens) more superficial layer

     clear film consisting of a sheet of small fibrils with little polysaccharide and no cells;


 - deep layer (cellular layer) w/ flattened chondrocytes;

     flat chondrocytes and collagen fibers are arranged tangentially to the articular surface;

25

Middle aka Intermediate aka transitional aka Zone II Cartilage

Type II collagen has an oblique or random organization


Is the thickest layer with round chondrocytes, and abundant proteoglycan content

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Deep layer aka Basal aka Radial aka Zone III Cartilage

 Type II collagen is perpendicular to joint and crosses tidemark

Round chondrocytes arranged in columns

High proteoglycan

27

Collagens of hyaline cartilage

II, IX, and XI go together

X (calcified cartilage)

VI (small amounts, tethers the chondrocyte to pericellular matrix)

28

"proteoglycan aggregate"

Many aggrecan molecules can bind to a chain of hyaluronate, forming macromolecular complexes that effectively are immobilized within the collagen network

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29

aggrecan

Sugar bonds link GAG to a long protein core to form a proteoglycan 

aggrecan then binds to HA to form proteoglycan aggregate

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30

glycosaminoglycans

made up of repeating disaccharide subunits

Chondroitin sulfate is the most prevalent GAG. With increasing age, chondroitin-4-sulfate decreases and chondroitin-6-sulfate remains constant.

 

Keratan sulfate increases with age

 

31

interaction of collagen and proteoglycan aggregates

Proteoglycans entangle between collagen fibers to create the fiber-reinforced solid matrix that helps determine the movement of water in the ECM 

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32

collagen orientation hyaline cartilage

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33

Calcified Cartilage (zone IV) Layer

radially aligned collagen fibers

 

round chondrocytes buried in a calcified matrix that has a high concentration of calcium salts and very low concentration of proteoglycans

Hypertrophic chondrocytes in this layer produce type X collagen and alkaline phosphatase, helping to mineralize the extracellular matrix

borders include the tidemark (upper)  and cement line (lower)

34

Hydroxylation of cartilage requires 

vitamin C

(occurs at ribosome, rough ER)

35

collagen synthesis figure II

Where does glycosylation occur?

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36

Commonly tested age vs OA changes in articular cartilage

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37

Synovium cell types

Type A is important in phagocytosis.


Type B comprises fibroblast-like cells that produce synovial fluid

38

major mode of lubrication of articular cartilage

Elastohydrodynamic 

39

Figure for articular cartilage degredation cascade

Key mediatior is IL1

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40

OA biochemical changes

OA is directly linked to a loss of proteoglycan content and composition with increased water content

 

Proteoglycans exist in shorter chains with an increased chondroitin/keratin sulfate ratio

Proteoglycans are largely unbound to hyaluronic acid because of proteolytic enzymes and decreased number of link proteins.

 

Collagen content is maintained, but its organization and orientation are severely disturbed, presumably due to collagenase

41

Molecular mechanisms of OA 

elevated proteolytic enzymes:  metalloproteinases (collagenase, gelatinase, stromelysin), cathepsins B and D


"Inflammatory cytokines"


IL-1

 

42

Articular cartilage components and percents

extracellular matrix (ECM) 95%, chondrocytes 5%

ECM:  water (65%-80%, remember higher at superficial layers), collagen (50% dry weight), proteoglycans

43

SMA

  • autosomal recessive, survival motor neuron (SMN) gene mutation

 

  • Hip Dislocation:  leave dislocated
  • Scoliosis:  PSF with fusion to pelvis, address hips first if contracture
  • Lower extremity contractures:  usually bracing occasionally releases for function and motivated pts

44

Friedreich's Ataxia:

genetics

manefestations

treatment

genetics:  AR, Frataxin, GAA repeats, mitochondria

manefestations: cavovarus foot, cardiomyopathy, scoliosis

treatment: 

scoliosis - 
PSF if curve > 60, rapid progression, predictors of progression (onset disease

foot -

standard CV operative treatment in early disease, ambulatory

triple if late dz, non-ambulatory

45

Larsen's Syndrome genetics

autosomal dominant (AD) and recessive (AR) inheritance patterns


AD linked to a mutation of the gene encoding filamin B


AR linked to carbohydrate sulfotransferase 3 deficiency

46

Larsen's Syndrome manefestations

ligamentous hyperlaxity, abnormal facial features, and multiple joint dislocations:  hips, knees (usually bilateral), shoulders, elbows (radial head)

 

hand deformities
scoliosis
clubfeet
cervical kyphosis

47

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Sprengel's Deformity

Associated diseases - Klippel-Feil (approximately 1/3 have Sprengel deformity), congenital scoliosis, upper extremity anomalies, diastematomyelia, kidney disease

Woodward procedure: detach, reattach at spine

Schrock, Green procedure:  detach, reattach at scapula

-- surgery 3 to 8 yrs of age if indicated, may need to do clavicle osteotomy

48

Marfan Syndrome manefestations

orthopaedic conditions
arachnodactyly
scoliosis (50%)
protrusio acetabuli (15-25%)
ligamentous laxity
recurrent dislocations (patella, shoulder, fingers)
pes planovalgus

nonorthopaedic conditions
cardiac abnormalities
aortic root dilatation
possible aortic dissection in future
mitral valve prolapse
superior lens dislocations (60%)
pectus excavatum
spontaneous pneumonthoraces
dural ectasia (>60%)
meningocele

49

Marfan Syndrome:

genetics 

treatment

AD, fibrillin

Scoliosis:

- bracing ineffective

- ASF+/- PSF, high rate complications

50

NF criteria (7)

Need 2 for diagnosis

 

1) Six or more café-au-lait macules measuring at least 0.5 cm in diameter (before puberty) or at least 1.5 mm in diameter (after puberty).
2) Two or more neurofibromas of any type OR one plexiform neurofibroma.
3) Freckling in the axillary or inguinal regions (skinfolds).
4) Optic pathway glioma.
5) Two or more Lisch nodules (iris hamartomas).
6) Dysplasia of the sphenoid bone, or dysplasia or thinning of the cortex of the long bones (e.g., tibia).
7) First-degree relative with NF.

51

Heparan N sulfatase deficiency

Sanfilippo syndrome (MPS III)
 

52

N-acteylgalactosamine-6-sulfatase deficiency

Morquio’s syndrome