Pediatric Syndromes Detailed

Question 1

Name 6 disproportionate dwarfisms

Answer 1

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

Question 2

Name 2 proportionate dwarfisms

Answer 2

cleidocranial, mucopolysacc

Question 3

Achondroplasia highlights (10)

Answer 3

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

Question 4

Apert’s (7 features)

Answer 4

• 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

Question 5

Answer 5

Apert

Question 6

SED highlights (6)

Answer 6

• short-trunk dwarfism
• COL2
• congenita (AD and severe)
• tarda (XLR and mild)
• AAI
• short stature, flattened facies, platyspondyly, kyphoscoliosis, coxa vara, genu valgum

Question 7

Conditions with AAI (6)

Answer 7

• Down syndrome
• neurofibromatosis
• Morquio syndrome
• spondyloepiphyseal dysplasia congenita

RA Klippel-veil

Question 8

Answer 8

• SED with AAI

Question 9

Answer 9

SED (platyspondyly )

Question 10

Kniest’s Dysplasia features (6)

Answer 10

• 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

Question 11

MED features

Answer 11

• 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

Question 12

Answer 12

MED

Question 13

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

Answer 13

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

Question 14

Jansen’s

Answer 14

• 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

Question 15

Schmid’s

Answer 15

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

Question 16

McKusicks

Answer 16

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

Question 17

Cleidocranial Dysplasia

Answer 17

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

Question 18

Diastrophic Dysplasia

Answer 18

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

Question 19

Answer 19

diastrophic dysplasia

Question 20

Osteogenesis imperfecta

Answer 20

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

Question 21

Gaucher Disease

Answer 21

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)

Question 22

zones of articular cartilage

Answer 22

Question 23

Superficial (Tangential) Zone Cartilage

Answer 23

• 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

Question 24

Superficial Zone Cartilage Sub-Layers

Answer 24

• fibrilar sheet (lamina splendens) more superficial layerclear 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;

Question 25

Middle aka Intermediate aka transitional aka Zone II Cartilage

Answer 25

Type II collagen has an oblique or random organization Is the thickest layer with round chondrocytes, and abundant proteoglycan content

Question 26

Deep layer aka Basal aka Radial aka Zone III Cartilage

Answer 26

Type II collagen is perpendicular to joint and crosses tidemark Round chondrocytes arranged in columns High proteoglycan

Question 27

Collagens of hyaline cartilage

Answer 27

II, IX, and XI go together X (calcified cartilage) VI (small amounts, tethers the chondrocyte to pericellular matrix)

Question 28

"proteoglycan aggregate"

Answer 28

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

Question 29

aggrecan

Answer 29

Sugar bonds link GAG to a long protein core to form a proteoglycan aggrecan then binds to HA to form proteoglycan aggregate

Question 30

glycosaminoglycans

Answer 30

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

Question 31

interaction of collagen and proteoglycan aggregates

Answer 31

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

Question 32

collagen orientation hyaline cartilage

Answer 32

Question 33

Calcified Cartilage (zone IV) Layer

Answer 33

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)

Question 34

Hydroxylation of cartilage requires

Answer 34

vitamin C | (occurs at ribosome, rough ER)

Question 35

collagen synthesis figure II Where does glycosylation occur?

Answer 35

Question 36

Commonly tested age vs OA changes in articular cartilage

Answer 36

Question 37

Synovium cell types

Answer 37

Type A is important in phagocytosis. ## Footnote Type B comprises fibroblast-like cells that produce synovial fluid

Question 38

major mode of lubrication of articular cartilage

Answer 38

Elastohydrodynamic

Question 39

Figure for articular cartilage degredation cascade

Answer 39

Key mediatior is IL1

Question 40

OA biochemical changes

Answer 40

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

Question 41

Molecular mechanisms of OA

Answer 41

elevated proteolytic enzymes: metalloproteinases (_collagenase, gelatinase, stromelysin_), cathepsins B and D ## Footnote "Inflammatory cytokines" IL-1

Question 42

Articular cartilage components and percents

Answer 42

extracellular matrix (ECM) 95%, chondrocytes 5% ECM: water (65%-80%, remember higher at superficial layers), collagen (50% dry weight), proteoglycans

Question 43

SMA

Answer 43

* 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

Question 44

Friedreich's Ataxia: genetics manefestations treatment

Answer 44

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

Question 45

Larsen's Syndrome genetics

Answer 45

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**

Question 46

Larsen's Syndrome manefestations

Answer 46

ligamentous hyperlaxity, abnormal facial features, and multiple joint dislocations: hips, knees (usually bilateral), shoulders, elbows (radial head) hand deformities scoliosis clubfeet cervical kyphosis

Question 47

Answer 47

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

Question 48

Marfan Syndrome manefestations

Answer 48

_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

Question 49

Marfan Syndrome: genetics treatment

Answer 49

AD, fibrillin ## Footnote Scoliosis: - bracing ineffective - ASF+/- PSF, high rate complications

Question 50

NF criteria (7)

Answer 50

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.

Question 51

Heparan N sulfatase deficiency

Answer 51

Sanfilippo syndrome (MPS III)

Question 52

N-acteylgalactosamine-6-sulfatase deficiency

Answer 52

Morquio’s syndrome