Bone disorders by Dr PC Anila Namboodiripad

9. The condition constitutes an uncommon, benign
fibro-osseous lesion that results in progressive,
painless, symmetrical expansion of the jaws with a
predilection for the mandible, and sometimes the
maxilla, resulting in a cherubic facial appearance.

10. These growths give the cheeks a swollen, rounded
appearance to resemble a ‘cherub’ and often interfere with
normal tooth development.
In some people the condition is so mild that it may not be
noticeable, while
other cases are severe enough to cause problems with
vision, breathing, speech, and swallowing.
Enlargement of the jaw usually continues throughout
childhood and stabilizes during puberty.
The abnormal growths are gradually replaced with normal
bone in early adulthood. As a result, many affected adults
have a normal facial appearance

11. Etiopathogenesis
Mutations in the SH3BP2 gene have been identified in
about 80 percent of people with cherubism.
In most of the remaining cases, the genetic cause of
the condition is unknown.
The SH3BP2 gene provides instructions for making a
protein whose exact function is unclear. The protein
plays a role as transcription factors within cells,
particularly cells involved in bone remodeling and
certain immune system cells.

12. Mutation of the gene encoding for fibroblast growth
factor receptor III (FGF-RIII) has also been found in
some cases of cherubism

13. The overactive protein likely causes inflammation in
the jaw bones and triggers the production of
osteoclasts.
This condition is inherited in an autosomal dominant
pattern,

14. Clinical features
Age: The age of onset of the symptoms is between 6
years and 10 years. And growth subsides as patient
reaches puberty.
Sex: M>F
Site: Maxillary and mandibular bone

15. The abnormal bone formation causes delayed
permanent tooth eruption
The teeth in the affected regions may be loose and
tooth eruption delayed. Premature primary teeth loss
and noneruption of permanent teeth due to the cysts
and other lesions are the manifestations
Absence of 2nd and 3rd mandibular molar
Maxillary arch has a ‘v’ shaped appearance.

17. Clinical features
jaw fullness due to the bilateral expansile masses with
symmetric involvement of mandible and maxilla
slight upward turning of eyes called as ‘heavenward
turning of the eyes’
Additionally submandibular lymph node enlargement
may also be present.

19. Grading system for cherubism
Arnott proposed a grading system for cherubism,
according to lesion location and the degree of expansion.
Accordingly,
grade 1 cases are limited to both ascending rami of the mandible;
grade 2 cases involve
the maxillary tuberosities and mandibular ascending rami (resulting in
congenital absence of the third and occasionally the second molars);
and grade 3 cases
correspond to massive involvement of both jaws except the coronoid
processes and condyles, resulting in considerable facial disfigurement.
Ramon and Engelberg added grade 4 in application to cases where all
of the classical features of the disorder exceeding grade 3 are present.
The grade may change depending on findings at follow-up examination

20. X-ray
All patients exhibited symmetrical multilocular
transparencies in the mandibular rami and angles.
Floating tooth syndrome.

21. Histopathology
Microscopy shows a highly vascular fibrous stroma with
unevenly distributed osteoclastic-like multinucleated giant
cells that tend to cluster near hemorrhagic foci and
deposits of hemosiderin.
Vascular channels are well formed and lined by large
endothelial cells.
The presence of eosinophilic, collagenous material around
small capillaries is of value in the diagnosis of cherubism
and is called as the Eosinophilic vascular cuffing
Mature lesions exhibit more dense fibrous tissue, while the
number of multinucleated giant cells decreases

23. D/D
Giant cell granuloma
Brown tumor of hyperparathyroidism.
Bone changes in hyperparathyroidism rarely cause
unilateral jaw lesions, but do produce abnormal serum
calcium and phosphorus levels.
In cherubism, eosinophilic collagen cuffing can be
observed and is pathognomonic for the lesion.
Aneurysmal bone cyst.

24. Treatment
Because cherubism is considered to be a self-limiting
condition that improves over time, treatment depends on
the individual patient’s functional and esthetic needs.
Most investigators prefer to wait until the end of puberty
before performing surgery.
Early surgical intervention is contraindicated because it
appears to predispose to recurrences.
Surgery is only indicated in cases characterized by
impaired speech, chewing or swallowing difficulties, or
with the presence of major deformities that may cause
psychological problems for the patient.

28. Paget disease of the bone (also known as osteitis
deformans) is a chronic bone disorder characterized
by excessive abnormal bone remodeling.
It was first described by Sir James Paget in 1877.

29. Etiology
Both genetic and environmental factors are thought to
play a role.
About 15% of people with Paget's disease have a family
history.
Autosomal dominant inheritance has also been
described in some families.
Mutations have been identified in four genes that
cause Paget's disease, of which sequestosome 1
(SQSTM1) mutation is the most important.

30. The mechanisms underlying the focal nature of the
disease are unclear.
Mechanical stress may play a role.
Paramyxovirus infection (including measles and
respiratory syncytial virus) has been suggested as a
possible trigger but this has been disputed

31. Clinical features
Age: Above 55 yrs of age
Sex: M>F=3:2
Site: Paget's disease can affect any bone but is most
common in the axial skeleton, long bones, and the
skull. The usual sites are the pelvis, lumbar spine,
femur, skull and tibia. The hands and feet are rarely
affected.
Paget's disease is very rare in Asian countries.
It is monostotic (affecting one bone) in a third of cases
and polyostotic (affecting two or more bones) in the
remaining two thirds.

32. Symptoms
localised pain and tenderness. Pain may be present at rest,
at night and on movement but does not tend to be focused
around a joint.
increased focal temperature due to hyperaemia (due to
hypervascularity)
increased bone size: historically changing hat size was a
give-away
bowing deformities
kyphosis of the spine
decreased range of motion
signs and symptoms relating to complications

33. Stages in paget’s disease
lytic (incipient active): predominated by osteoclastic
activity
mixed (active): osteoblastic as well as osteoclastic
activity
sclerotic/blastic (late inactive)

34. X ray
osteoporosis circumscripta: large well defined lytic
lesion
cotton wool appearance: mixed lytic and sclerotic
lesions of skull
diploic widening: both inner and outer calvarial tables
are involved.
Long bones show blade of grass or candle flame
sign: begins as a subchondral area of lucency with
advancing tip of V shaped osteolysis extending
towards the diaphysis.

35. There is a lytic phase to the disease process with an
increase in bone resorption and abnormal osteoclast
activity. This leads to a rapid increase in bone
formation by osteoblasts. In the sclerotic phase, the
focus is on bone formation.
The structure of this new bone is disorganised and it is
mechanically weaker, more bulky, less compact, more
vascular, and liable to pathological fracture and
deformity.

39. Complications
neural compression may result in
deafness is the most common complication
cranial nerve paresis may occur
basilar invagination may occur in advanced cases
with hydrocephalus orbrainstem compression
secondary development of tumours like osteosarcomas

40. Histopathology
woven bone and irregular broad
trabeculae with disorganized cement lines in a mosaic
pattern
profound bone resorption - numerous
large osteoclasts with multiple nuclei per cell
virus-like inclusion bodies in osteoclasts
Paget's osteoclasts larger, more nuclei than typical
osteoclasts
fibrous vascular tissue interspersed between
trabeculae

43. Lab diagnosis
serum alkaline phopatase (ALP) elevated
urine hydroxyproline increased.
Serum calcium, phosphorus, and parathyroid
hormone levels are usually normal but immobilisation
may lead to hypercalcaemia.
Urinary excretion of deoxypyridinoline and N-
telopeptide are elevated.

44. Treatment
The objectives of treatment are control of pain and to
reduce or prevent disease progression and complications.
Non-steroidal anti-inflammatory drugs (NSAIDs) and
paracetamol may be effective for pain.
Anti-resorptive therapy is with either bisphosphonates or
calcitonin (now rarely used).
Any calcium and vitamin D deficiency needs to be
corrected before starting a bisphosphonate to avoid
hypocalcaemia.
Osteonecrosis of the jaw has been reported in patients
taking bisphosphonates for Paget's disease

60. Cleidocranial dysostosis
Cleidocranial dysplasia primarily affects the
development of the bones and teeth.
Signs and symptoms of cleidocranial dysplasia can
vary widely in severity, even within the same family.

61. Pathogenesis
caused by defect in intramembranous ossification
leads to failure of formation of midline structures
characteristic feature is hypoplastic or absent clavicles
autosomal dominant
RUNX2/CBFA1 mutation
transcription factor which regulates osteoblastic
differentiation

63. Clinical features
proportionate dwarfism
clavicle dysplasia/aplasia
wormian or sutural bones
frontal bossing
delayed fontanel ossification
due to delay in closure of skull sutures
shortened middle phalanges of 3-5 fingers
delayed ossification of pubis
dental abnormalities
delayed eruption of permanent teeth

68. Physical exam
hypermobility of the shoulders
abnormal range of motion at hips

69. X-ray
AP chest
clavicular dysmorphism
lateral skull
delayed closure of sutures
AP pelvis
coxa vara
failure of pubis to ossify

70. Symptoms
Symptoms
usually asymptomatic

71. Treatment
Surgery if condition interferes with normal
functioning.

73. Fibrous dysplasia shows a tumor-like proliferation of
fibro-osseous tissue.
The cause of fibrous dysplasia is unknown. It may
either present as monostotic, affecting one bone, or
polyostotic, affecting many bones

74. The tissue in the tumor is immature, woven bone that
cannot differentiate into mature, lamellar bone.
Mutation in the GNAS 1 (guanine nucleotide
binding protein alfa stimulating activity polypeptide)
gene playing a role in osteoblastic and osteoclastic
differentiation. This results in increased cAMP in all
the affected tissues. Endocrine glands produces a
rapid implementation of secondary sexual
characteristics.

75. This is a somatic mutation, rather than in the
germline.
It results from a defect is somatic mutation in the gene
coding for alpha subunit of Gs, the G protein that
stimulates cAMP formation;
- overproduction of cAMP, causes overexpression
of c-fos, which regulates proliferation and
differentiation of osteoblasts and osteoclasts;

76. The abnormality is limited to the tissues within the
lesions.
The cells have increased number of hormone
receptors, which may explain why these lesions
become more active during pregnancy

77. Patients who have increased pain in their fibrous
dysplasia lesions linked to their monthly menstrual
cycle.

78. Clinical features
Age: <30 years of age
Sex: M=F
Site: Monostotic : single bone
Polyostotic: multiple bones especially long bones.

79. Clinical features
Also, polystotic fibrous dysplasia is known to have multiple
associations with other disorders. The combination of
polyostotic fibrous dysplasia, precocious puberty, and cafe
au lait spots is called Albright's syndrome.
The association of fibrous dysplasia and soft tissue tumors
has been given the name Mazabraud's syndrome.
Other endocrine abnormalities including hyperthyroidism,
Cushing's disease, thyromegaly, hypophosphatemia, and
hyperprolactinemia have been associated with fibrous
dysplasia.

80. Monostotic fibrous dysplasia may be completely
asymptomatic and is often an incidental finding on x-
ray.
Pain and swelling at the site of the lesion can also be
present.
Unfortunately, this tumor can also present as a
pathological fracture that is followed by a nonunion or
malunion.

81. Classification
monostotic: single bone
polyostotic: multiple bones
craniofacial fibrous dysplasia: skull and facial bones
alone
cherubism: mandible and maxilla alone (not true
fibrous dysplasia)

82. Monostotic
This is by far the most common and accounts for 70-
80% of cases .
It is usually asymptomatic until 2nd-3rd decade, but can
be seen throughout adulthood . 10-70 yrs of age.
F>M
After puberty the disease becomes inactive, and
monostotic form does not progress to polyostotic
form.

83. Pain and swelling of the jaws.
Rarely seen in oral cavity.
But if present in maxilla there is maxillary swelling
which produces the bulging of the canine fossa to
extend right upto the tuberosity. This appearance of
the face is called as ‘leontiasis ossea’. Expansion is
more on the buccal than the lingual side. In case of the
mandible the lower border is protruberant.
Cortical plate is intact and so is the covering mucosa.
Malalignment of teeth.

84. Xray
Unilocular or multilocular. It has a thick margin called
as the ‘rind’ sign.
Mottled appearance
Ground glass or ‘peau d orange’
But the cortical plate is never perforated.
Teeth may flared out and only sometimes is there a
resorption.

85. Shepherd crook deformity.

86. Polyostotic
In the remaining 20-30% of cases multiple bones are
involved.
This presents earlier, typically in childhood (mean age
of 8 years) with 2/3rds that become symptomatic by the
age 10.

87. Endocrinal changes
Precocious puberty
Bone manifestations
Café au lait spots. May occur at birth and precede
skeletal development. Jaffe’s type

88. Histopathology
irregular foci of woven bone arising from a cellular
fibrous stroma.
The stroma has a whorled appearance and
is highly vascular.
The short, irregular bone segments or trabeculae are
not rimmed by osteoblasts.
These irregular trabeculae have been described as
"Chinese letters" or "alphabet soup".
No lamellar bone is found within a fibrous dysplasia
lesion.

89. Lab diagnosis
Increased alkaline phosphatase
Premature secretion of FSH.

90. D/D
Ossifying fibroma:

91. Treatment
Painful long bone lesions can be stabilized by cortical
grafting or implant fixation.
Curettage and bone grafting alone is best suited to
lesions in non-weight bearing bones