ACHONDROPLASIA THANATOPHORIC DYSPLASIA OSTEOGENESIS IMPERFECTA OSTEOPETROSIS

Genetic Abnormality 90% from new mutations in Mutations in FGFR3 Mutation in the gene COL1A1 or Mutation in the TCIRG1 gene
paternal allele COL1A2 that encode the a1 and a2 (encodes components of a vacular
chains of type I collagen ATPase that helps to maintain acidic
pH in osteoclasts)
Type of Gene Defect Autosomal dominant Autosomal dominant Autosomal dominant Autosomal recessive mutation
(autosomal/sex- in the enzyme carbonic anhydrase 2
linked; (CA2)
dominant/recessive)
Pathology FGF inhibits endochondral growth Results from diminished decreased bone collagen  extreme Osteoclasts fail to remove primary
 mutation will cause inability to proliferation of chondrocytes and skeletal fragility (brittle bones) spongiosa bone  accumulate and
convert cartilage bone disorganization in the zone of make bone appear very dense
proliferation radiographically, lacking medullary
canal but are biomechanically vert
weak which results in frequent
pathologic features.
Manifestation (based -Short stature -marked bilateral shortening of the -blue sclerae due to translucent -Erlenmeyer flask deformity of the
on type) -Shortened proximal extremities limbs (micromelia) redundant skin sclera from decreased collagen epiphysis
-A trunk of relatively normal length folds content -nerve compression due to small
-Enlarged head with bulging -frontal bossing with relative Sensorineural hearing loss due to neural foramina
forehead macrocephaly abnormalities in the bones of the -anemia & leukopenia due to
-Conspicuous depression of the root -flat faces with low nasal bridge middle ear absence of red bone marrow from
of the nose and prototic eyes -dentinogenesis imperfecta  dental the persistence of primary spongiosa
-NO changes in longevity, -a small bell-shaped chest cavity & imperfections (small misshapen and
intelligence or reproductive status hypoplastic lungs blue-yellow teeth) secondary to
-bell-shaped abdomen  repiratory deficiency in dentin
insufficiency
-die after birth or soon after
Prognosis

DEFECTS DISORDERS OF BONE AND CARTILAGE

- Developmental abnormalities of the skeleton are frequently the result of inherited mutations and first become manifest during the earliest stages of bone formation. In contrast,
acquired diseases are usually detected in adulthood.

 Developmental anomalies can result from localized problems in the migration and condensation of mesenchyme (dysostosis) or global disorganization of bone and/or cartilage
(dysplasia).
DEFECTS IN NUCLEAR PROTEINS AND TRANSCRIPTION FACTORS
- Defects in nuclear proteins and transcription factors, especially homeobox proteins, cause disorganized mesenchymal condensation and abnormal differentiation of osteoblasts and
chondrocytes. These defects manifest as abnormally developed bones.
 Brachydactyly types D and E - caused by mutation in the homeobox HOXD13 gene, produces shortening of the terminal phalanges of the thumb and big toe.
 Loss-of-function mutations in the RUNX2 gene - result in cleidocranial dysplasia, an autosomal dominant disorder characterized by patent fontanelles, delayed closure of cranial
sutures, Wormian bones (extra bones that occur within a cranial suture), delayed eruption of secondary teeth, primitive clavicles, and short height.

DEFECTS IN HORMONES AND SIGNAL TRANSDUCTION PROTEINS

1. ACHONDROPLASIA
- Is the most common skeletal dysplasia and a major cause of dwarfism
- An autosomal dominant disorder resulting in retarded cartilage “without cartilage formation”
- Cause by gain-of-function mutations in the FGF receptor 3 (FGFR3). Normally, FGF-mediated activation of FGFR3 inhibits endochondral growth. Constitutive activation of
FGFR3 exaggerates this effect, suppressing growth.

2. THANATROPHIC DYSPLASIA
- Is the most common lethal form of dwarfism, affecting about 1 in every 20,000 live births
- The histologic changes ii the growth plate show diminished proliferation of chondrocytes and disorganization in the zone of proliferation.
- Caused by the gain-of-function mutations in the FGF receptor 3 (FGFR3), that differ from those of achondroplasia

TYPES:
1) Type I –marked by the presence of thigh bone curvatures (telephone handle femur) and a flattening of the person’s spine bones, referred to as “platyspondyly”
2) Type II – marked by thigh bones which are straight, limb shortening is milder, moderate to severe abnormality of the person’s skull  “cloverleaf skull”

3. ABNORMAL BONE DENSITY

- Abnormal bone density can result from mutations in the genes that regulate osteoclast differentiation or osteoclast function
- Caused by either osteoporosis (too little bone) or osteopetrosis (too much)
 adults: specific mutations in the gene for the receptor LPR5 can manifest either osteoporosis or osteopetrosis
 infantile form: osteopetrosis is associated with mutation of RANKL, resulting in decreased or absent osteoclasts
 animals: osteopetrosis can be caused by mutation in M-CSF and OPG, which regulate osteoclast formation and function
DEFECTS IN EXTRACELLULAR STRUCTURAL PROTEINS
I. TYPE I Collagen Disease (OSTEOGENESIS IMPERFECTA)
- Or brittle bone disease, is a phenotypically diverse disorder caused by deficiencies in the synthesis of type I collagen
- Most common inherited disorder of connective tissue
- Affects bone and tissue rich in type I collagen (joints, eyes, ears, skin and teeth)
- Autosomal dominant by COL1A1 or COL1A2 that encode the a1 and a2 chains of type I collagen  cause misfolding of the mutated collagen polypeptides and they
interfere with the proper assembly of type I collagen
- Functional abnormality: decreased bone collagen  extreme skeletal fragility (brittle bones)
 TYPES:
1) Type I
– most common form & mildest where individuals secrets about half the normal amount of Type I procollagen
- with increased risk of fracture especially during childhood but has normal length and lifespan and usually born without deformities
2) Type II – severe, usually lethal in the perinatal period owing to severe fractures and deformity
3) Type III & IV
- survive fractures in infancy and childhood but have progressive deformity
III  is severe nonlethal form, characterized by sclera of normal color, multiple birth fractures and significant long-term deformity and disability
IV  is the intermediate form, with variable manifestations and is the least common

DEFECTS IN METABOLIC PATHWAYS (Enzymes, Ion Channels and Transporters)

1) OSTEOPETROSIS
- Also known as marble bone disease and Albers-Schonberg Disease
- Refers to a group of rare genetic diseases that are characterized by reduced bone resorption and diffuse symmetric skeletal sclerosis due to impaired formation or function
of osteoclass  stone-like quality of the bone that lack medullary cavity with bulbous and misshapen epiphysis (Enlenmeyer flask deformity)
Pathogenesis:
 Osteoclasts fail to remove primary spongiosa bone  accumulate & make bone appear very dense radiographically, lacking a medullary canal but are biomechanically
very weak which results in frequent pathologic fractures.
 Severe infantile osteopetrosis
- autosomal recessive
- becomes evident in utero or soon after birth
- Fracture, anemia, and hydrocephaly are often seen, resulting in postpartum mortality.
- Affected individuals who survive into their infancy have cranial nerve defects (optic atrophy, deafness, and facial paralysis) and repeated—often fatal—infections
because of leukopenia, despite extensive extramedullary hematopoiesis that can lead to prominent hepatosplenomegaly.
 Mild autosomal dominant form
- may not be detected until adolescence or adulthood, when it is discovered on x-ray studies performed because of repeated fractures.
- these individuals may also have mild cranial nerve deficits and anemia
DISEASES ASSOCIATED WITH DEFECTS IN DEGRADATION OF MACROMOLECULES
1. Mucopolysaccharidoses
o are a group of lysosomal storage diseases that are caused by deficiencies in the enzymes that degrade dermatan sulfate, heparan sulfate, and keratan sulfate
o affected enzymes are mainly acid hydrolases
o in these diseases, mucopolysaccharides accumulate inside the chondrocytes, causing apoptotic death of the cells, and also in the extracellular space, resulting in
structural defects in articular cartilage
o abnormalities in hyaline cartilage, including the cartilage anlage, growth plates, costal cartilages, and articular surfaces.
o affected individuals are frequently of short stature and have chest wall abnormalities, and malformed bones 4
 4
Enumerate the BENIGN bone-forming tumors
TUMOR TYPE LOCATION MORPHOLOGY AGE X-RAY FINDINGS PROGNOSIS METASTASIS
1. osteoid metaphysis of long Cortical, interlacing 10-20 thick rind of reactive No risk of metastasis
osteoma bones (arise between microtrabeculae of (75%-80% of pt < 25 cortical bone
the periosteum or in woven bone y/o)
the cortex in the Rarely over 30 years
proximal femur and
tibia)
2. osteoblastoma Vertebral column Posterior elements of 10-20 Larger and have Aggressive type of
(50% in spine (post.) vertebra, histology osteolytic and sclerotic osteoblastoma (very
& skull; also in long similar to osteoid border rare) led to metastasis,
bones – humerus, tibia, osteoma death and mimic
femur) osteosarcoma

Enumerate the MALIGNANT bone-forming tumors

TUMOR TYPE LOCATION MORPHOLOGY AGE X-RAY FINDINGS PROGNOSIS METASTASIS
1. osteosarcoma Metaphysis of distal Extends from medulla 10-20 A triangular shadow 5-year survival rates 10% to 20%pulmonary
femur, proximal tibia to lift periosteum, (75% occur in persons between the cortex and reaching 60% to 70% metastases
malignant cells younger than 20 years raised periosteum in patients without 90% have metastases
producing woven bone of age) (Codman triangle) overt metastases at to the lungs, bones,
smaller second peak initial diagnosis brain, and elsewhere
occurs in older adults, Unfortunately, the
who frequently suffer outcome for patients
from conditions known with metastases,
to predispose to recurrent disease or
osteosarcoma—Paget secondary
disease, bone infarcts, osteosarcoma is still
and prior radiation poor (<20% 5-year
survival rate).
2.
Enumerate the BENIGN cartilage-forming tumors
TUMOR TYPE LOCATION MORPHOLOGY AGE X-RAY FINDINGS PROGNOSIS METASTASIS
1. Esteochondrom Metaphysis of long Bony excrescence with 10-30 Cartilage-capped bony No propensity for
a bones cartilage spur on the surface of metastasis
“exostosis” (knee occasionally, the bone (mushroom-
they develop from appearance)
bones of the pelvis,
scapula, and ribs,)
2. Chondroma Small bones of hands Circumscribed hyaline 20-50 radiographic features
and feet cartilage nodule in consist of
medulla circumscribed
lucencies with central
irregular calcifications,
a sclerotic rim and an
intact cortex

Enumerate the MALIGNANT cartilage-forming tumors

TUMOR TYPE LOCATION MORPHOLOGY AGE X-RAY FINDINGS PROGNOSIS METASTASIS
1. Chondrosarcom Pelvis, Shoulder Extends from medulla 50-60 calcified matrix grade 1 tumors with 5- Grade 1
a (conventional) through cortex into appears as foci of year survival rates of chondrosarcomas
soft tissue, flocculent densities 80% to 90% (versus rarely metastasize,
chondrocytes with 43% for grade 3 whereas 70% of grade
increased cellular and tumors) 3 tumors spread
atypia hematogenously
especially to lungs and
skeleton
2.
Enumerate the BENIGN tumors of unknown origin
TUMOR TYPE LOCATION MORPHOLOGY AGE X-RAY FINDINGS PROGNOSIS METASTASIS
1. Giant cell Epiphysis of long Destroys medulla and 20-40 Large, lytic, “soap- treated with curettage, Up to 4% of tumors
tumor bones cortex, sheets of bubble” lesion but 40% to 60% recur metastasize to the
osteoclasts locally lungs, but these
sometimes
spontaneously regress
and they are seldom
fatal
2. Aneurysmal Proximal tibia, distal Vertebral body, 10-20 Eccentric, expansile, treatment is surgical,
bone cyst femur, vertebra hemorrhagic spaces lytic, metaphyseal (curettage or en bloc
separated by cellular, lesion with well- resection)  the
fibrous septae defined margins recurrence rate is low,
(CT scan and MRI and spontaneous
may demonstrate regression may occur
internal septa and following incomplete
characteristic fluid- removal
fluid levels)

Enumerate the MALIGNANT tumors of unknown origin

TUMOR TYPE LOCATION MORPHOLOGY AGE X-RAY FINDINGS PROGNOSIS METASTASIS
3. Ewing’s Diaphysis of long Sheets of primitive 10-20 Flat bones: destructive chemotherapy has Found in 30% cases
sarcoma bones small round cells lesion with a large soft achieved 5-year most commonly in the
tissue component survival of 75% and lungs & other bones &
Long bones: lytic long-term cure in 50% less commonly the
medullary lesion bone marrow
(moth-eaten Associated with
appearance) with visceral, lymphatic and
periosteal elevation or meningeal
“onion skinning” involvement
4.