Pediatric Syndromes Detailed Flashcards
Name 6 disproportionate dwarfisms
Achondroplasia, MED, SED, DD, Kniest, metaphyseal chondrodysplasia
Name 2 proportionate dwarfisms
cleidocranial, mucopolysacc
Achondroplasia highlights (10)
- autosomal dominant - FGFR3 - activating mutation proliferative zone physis - spinal stenosis (C and L) - TL kyphosis - rhizomelic - genu varum
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
Apert
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
Conditions with AAI (6)
- Down syndrome
- neurofibromatosis
- Morquio syndrome
- spondyloepiphyseal dysplasia congenita
RA Klippel-veil
- SED with AAI
SED (platyspondyly )
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
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
MED
What physeal area is affected in the Metaphyseal Chondrodysplasias (Jansen, Schmid, McKusic)?
- proliferative and hypertrophic zone of the physis (epiphysis is normal)
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
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
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
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
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
diastrophic dysplasia
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
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)
zones of articular cartilage
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
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;
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
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
Collagens of hyaline cartilage
II, IX, and XI go together
X (calcified cartilage)
VI (small amounts, tethers the chondrocyte to pericellular matrix)
“proteoglycan aggregate”
Many aggrecan molecules can bind to a chain of hyaluronate, forming macromolecular complexes that effectively are immobilized within the collagen network
aggrecan
Sugar bonds link GAG to a long protein core to form a proteoglycan
aggrecan then binds to HA to form proteoglycan aggregate
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
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
collagen orientation hyaline cartilage
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)
Hydroxylation of cartilage requires
vitamin C
(occurs at ribosome, rough ER)
collagen synthesis figure II
Where does glycosylation occur?
Commonly tested age vs OA changes in articular cartilage
Synovium cell types
Type A is important in phagocytosis.
Type B comprises fibroblast-like cells that produce synovial fluid
major mode of lubrication of articular cartilage
Elastohydrodynamic
Figure for articular cartilage degredation cascade
Key mediatior is IL1
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
Molecular mechanisms of OA
elevated proteolytic enzymes: metalloproteinases (collagenase, gelatinase, stromelysin), cathepsins B and D
“Inflammatory cytokines”
IL-1
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
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
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
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
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
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
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
Marfan Syndrome:
genetics
treatment
AD, fibrillin
Scoliosis:
- bracing ineffective
- ASF+/- PSF, high rate complications
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.
Heparan N sulfatase deficiency
Sanfilippo syndrome (MPS III)
N-acteylgalactosamine-6-sulfatase deficiency
Morquio’s syndrome
