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Skeletal Disorders (CAUSES
Abnormal quantity or quality of cartilage…
Skeletal Disorders
CAUSES
Abnormal quantity or quality of cartilage structural proteins
Inborn errors of cartilage metabolism
Defects in local regulators of cartilage growth
Systemic defects influencing cartilage development
Peroxismal disorders
Transcription
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Structural Proteins of Cartilage
*Type II collagen
COL2A1 gene
Type IX collagen
COL91A
COL92A
COL93A
Type X collagen
COL10A1
Type XI collagen
COL11A2
Cartilage Oligometric Matrix Protein - COMP
Type XI Collagen
- expressed in the inner ear and parts of the eye
- disorders in this collage can have deafness and vision problems
TYPE XI COLLAGEN DISORDERS
- Fibrochondrogenesis (pulmonary hypoplasia or respiratory insufficiency is common cause for death; very rare; autosomal recessive)
- Stickler syndrome
- Marshall syndrome
- Osteoarthritis
- Degenerative disc disease
Type II Collagen
- Type II collagen makes up 85% of hyaline cartilage
- hyaline cartilage is what initially comprises the skeleton of the fetus
- these areas will eventually turn to bone
- present in the growth plates
- present in joint articulation, allows you to move without pain
TYPE II COLLAGEN DISORDERS
- Stickler syndrome
- Spondyloepiphyseal dysplasia congenita
- Achondrogenesis-hypochondrogenesis type II
- Kniest Dysplasia
- Spondylometaphyseal dysplasia
Kniest Dysplasia
- short stature
- short trunk
- shortened arms and legs
- 42 inches to 58 inches (4-5 ft)
- macrocephaly
- platyspondyly
- joint enlargement
- joint limitation
- lordosis
- atlanto-axial instability
- instability of the cervical spine
- big cause of mortality
- myopia
normal lifespan
no developmental delay or ID
rare, no known incidence
autosomal dominant 
Inborn Errors of Cartilage Metabolism or FormationDiastrophic Dysplasia Sulfate Transporter - DTDST
- SLC26A2
- This gene product transports sulfate ions across cell membrane
- cartilage use these to form proteoglycans which are important in bone formation
- Achondrogenesis Type IB
- Atelosteogenesis Type II
Heparin Sulfate Proteoglycan Type 2 - HSPG2
- Schwartz Jampel Syndrome Type I
- Dyssegmental Dysplasia
Arylsulfatase E - ARSE
- Chondrodysplasia Punctata (XL)
Cartilage-derived Morphogenetic Protein - CDMP1
- Chondrodysplasia, Grebe type
- Brachydactyly types A2 and C
- Acromelic dysplasia, Hunter-Thomson type
Diastrophic Dysplasia
- Somewhat normal lifespan
- Disproportionate short stature
- Mesomelic dwarfism
- Micromelia
- progressive joint contractures
- progressive dysplasia of the hips (~75% of cases)
- small chests, protuberant abdomen
- Clubfeet (almost all cases)
- "Hitchhiker's thumb" (almost 100% of cases)
- thumb is displaced very low
- Cauliflower ear
- very specific to this disorder
- ~85%
- Cleft palate
SLC26A2
- Autosomal recessive
- 1 in 500000
Achondrogenesis Type 1b
severe phenotype
individuals die at the time of birth, in utero, or shortly after birth
- SLC26A2
- Small body
- Short limbs
- Protuberant abdomen
- Hydrops fetalis
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Evaluation of Skeletal DysplasiasWhen you suspect a SD, order a skeletal survey
- X-rays
- Some specific skeletal findings that can point you in one direction or another
- OI, you'd find fractures or healed fractures
- Constitutional Abnormalities, you might find bowing
Family and Medical HistoryPhysical Exam
- Growth parameters, proportions
- Dysmorphic features
- Anomalies
Genetic Counseling
- Variable severity
- Variable Life Expectancy
- Achondroplasia vs Thanatophoric dysplasia
- Diastrophic dysplasia vs achondrogenesis
- Many are AD
- high de novo rates
- advanced paternal age
- homozygous offspring
Support organizations - Little People of America
FEATURES
- Short stature
- growth charts exist for some dysplasias
- proportionate or disproportionate?
- is it due to their limbs being short? and their trunk is normal? or is the trunk short? what is accounting for that short stature? because that can be a clue to the underlying etiology of the short stature
- Macrocephaly
- is it true or relative macrocephaly?
- true macrocephaly > 90% on normal growth chart
- relative macrocephaly > 75% on normal growth chart but their height is below 2% on normal growth chart
- Limb abnormalities
- Small chest
- Abnormal bones
- some disorders have specific bone abnormalities that will help you diagnose
OTHER FINDINGSHEAD
- frontal bossing
- flat facies; flat nasal bridge
- cloverleaf skull
- congenital cataracts
- myopia
- palate abnormalities
- bifid uvula
- short and tethered upper lip
CHEST
- long and narrow, or small thorax
- scoliosis
Associated Features
- Cardiac defects
- GI abnormalities
- kidney problems to ambiguous genitalia
SKELETAL SURVEY
What to do when you suspect a skeletal dysplasia?
an infant can be done in one picture
- AP and lateral skull
- AP and lateral spine
- AP pelvis
- AP extremities
- AP hands
- AP and lateral feet
Bone formation occurs later in development which can make prenatal detection not occur until later stages in the pregnancyBones change over time; periodice skeletal surveys can be informative
ANATOMY
- Bones have 3 distinct sections
- Epiphysis
- Metaphysis
- Diaphysis
from tip to tip bones are arranged: E > M > D > M > E
- growth plate between epiphysis and metaphysis
- white appearance on scan indicates active growth
- when the growth plate has ceased to produce bone, i.e., you've reached your height, the epiphysis and metaphysis will fuse together
- premature fusion of the growth plate, or premature ending to bone production, it can result in bones that are not the appropriate length
Bone Formation
aka osteogenesis aka ossification aka bone remodeling
- In the literature, it's described as a replacement process
Two types of processes:
Can be thought of as a continuum
- Mesenchymal tissue present at development that can change to cartilage then to bone, or simply skips the cartilage stage and goes straight to bone
MEMBRANOUS
- No cartilage present, osteoblasts differentiate directly from the mesenchymal tissue
- Healing of bone fractures
- Rudimentary formation of the bones of the head (flat bones)
- predominantly bones in the head, skull, craniofacial bones
ENDOCHONDRAL
- Cartilaginous model
- goes through the cartilage phase
- mesenchymal cells differentiate into chondrocytes, secrete the cartilaginous matrix (type II collagen) , proliferate, differentiate , resorption and then become osteoblasts
- things that are important in this process: osteocalcin, growth factors, etc
- become every other bone in the skeleton essentially
TERMINOLOGY
Osteo = bone
Chondro = cartilage
Osteochondrodysplasia - disorders where bone or cartilage grows abnormallyEpiphyseal - involves the epiphyses of long bones
Metaphyseal - involves the metaphyses of long bones
Spondylo - involves the vertebraeRhizomelic - proximal
Mesomelic - middle
Acromelic - distal (hands and feet)Micromelic - all/everything, not any
GROUPS OF DISORDERSAbnormal growth/development of cartilage/bone
- can be generalized abnormal growth/development
- can be individual bones
- ex: Klippel Feil (cervical vertebrae), Sprengel deformity (scapula), Nail-Patella
Overgrowth disorders involving the skeleton
Disorders of decreased bone density
Disorders of increased bone density
Syndromes/metabolic diseases that include skeletal abnormalities