For Orthopaedicians and UnderGraduates

1. Congenital
Malformations Of Bone
(Skeletal Dysplasia)
Dr. Apoorv Jain
D’Ortho, DNB Ortho
drapoorvjain23@gmail.com
+91-9845669975

2. • The Word dysplasia originates from
the ancient greek words
dys(anomalous) & plasia(formation)
• Skeletal dysplasia is a heterogeneous
group of congenital anomalies
characterized by the abnormalities
in the development of Bone and
cartilagenous tissues

3. Normal Bone Development
On the basis of development, the bones are of 2
types:
• Intramembranous bones
• Endochondral bones
Intramembranous
Ossification: Bone is directly
laid down in membranous
sheets without any
cartilaginous model
(Eg: Clavicle, Facial bones
and Bones of the Skull vault)

4. Endochondral Bones: The formation of bone is
preceded by the formation of a cartilaginous bone
model which is replaced by bone (Eg: Bones of the
limbs except clavicle, trunk and base of the skull)

5. Classification Of Skeletal Malformations
(By Agerter and Kirkpatrick, 1975)
1) Disturbances in Chondroid Production:
Abnormal Maturation of Chondroblasts:
•Mucopolysaccharidosis
•Idiopathic:
–Achondroplasia
–Cartilage-Hair Hypoplasia
–Metaphyseal Dysostosis

6. Heterotopic Proliferation Of
Chondroblasts:
-Enchondromatosis
(Dyschondroplasia , Ollier’s disease)
-Osteochondromatosis
(Multiple Heriditary Exostosis)
-Epiphyseal Hyperplasia

7. 2. Disturbances in Osteoid production:
A) Abnormal Epiphyseal Ossification:
-Diastrophic Dwarfism
-Spondyloepiphyseal Dysplasia
-Multiple Epiphyseal Dysplasia
(Includes Blount’s and Pseudochondroplasia)
-Stippled Epiphysis

8. B) Abnormal Metaphyseal and Periosteal
Ossification:
1) Deficient Osteoid Production:
-Osteogenesis Imperfecta
2) Excessive Osteoid production or Decreased
Osteolysis:
-Osteopetrosis
-Pykindysostosis
-Metaphyseal Dysplasia
-Diaphyseal Sclerosis
-Melorheostosis
-Osteopathia Striata
-Osteopoikilosis

9. C) Abnormal Osteoid Production:
-Polyostotic Fibrous Dysplasia
-Neurofibromatosis
-Congenital Pseudoarthrosis
3) Miscellaneous Dysplasias:
 Marfan’s Syndrome
 Apert’s Syndrome
 Cleidocranial Dysostosis
 Chondroectodermal Dysplasias

10. EVALUATION OF A
PATIENT WITH
SKELETAL DYSPLASIA

11. Prenatal Diagnosis
• Prenatal Ultrasound– Identify
lethal dysplasias
–Diagnosis based on femoral length,
head circumference, body ratios and
fetal characteristics typical of skeletal
dysplasias
• Genetic analysis
–Chorionvillous biopsy
–Amniocentesis

12. Postnatal Diagnosis
THREE CLINICAL QUESTIONS:
• Is the child abnormally small or
large?
• Is stature proportional or
disproportional?
• Dysmorphic facial features?

13. • Short Limb
–Achondroplasia
–Hypochondroplasia
–Chondrodysplasia punctata
–Achondrogenesis
–Thanatophoric dysplasia
• Short Trunk/limb
–Spondyloepiphyseal dysplasia

14. Long Bones:
• The long bones in all of the extremities
should be measured.
• If limb shortening is present, the
segments involved should be defined.
• A detailed examination of the involved
bones is necessary to exclude absence,
hypoplasia, and malformation of the
bones.

15. • The bones should be assessed for
presence, curvature, degree of
mineralization, and fractures.
• The femur length–abdominal
circumference ratio (<0.16 suggests lung
hypoplasia) and femur length–foot
length ratio (normal = 1, <1 suggests
skeletal dysplasia) should be calculated.

17. Thorax:
• The chest circumference and
cardiothoracic ratio should be measured
at the level of the nipples or 5th
intercostal space.
• A chest circumference less than the 5th
percentile for gestational age (8–10) has
been proposed as an indicator of
pulmonary hypoplasia.

18. The chest diameter should be between 80-100%
of the abdominal diameter.

19. • The shape and integrity of the thorax
should be noted.
• Abnormal rib size and configuration are
also seen in patients with lethal skeletal
dysplasias.
• The clavicles should be measured, since
absence or hypoplasia of the clavicles is
seen in cleidocranial dysplasia.
• The presence of the scapula should also be
noted, since its absence is a useful defining
feature of camptomelic dysplasia.

20. Hands and Feet:
The hands and feet should be evaluated to
exclude the presence of
(a) Polydactyly (the presence of more than five
digits)
[Preaxial if the extra digits are located on the
radial or tibial side and postaxial if they are
located on the ulnar or fibular side]
(b) Syndactyly (soft-tissue or bone fusion of
adjacent digits).
(c) Clinodactyly (deviation of a finger) and other
deformities.

21. Example Of Post-axial Polydactyly

22. Bony Syndactyly Clinodactyly

23. • “Radial-ray” anomalies range from abnormal thumbs to
hypoplasia or absence of the thumb and sometimes
absence of the radius or even the radius and the hand.
• The three most likely diagnoses include:
Holt-Oram syndrome, the thrombocytopenia-
absent radius (TAR) syndrome and trisomy 18.

24. Skull:
• Head circumference and biparietal
diameter should be measured to exclude
macrocephaly.
• The shape, mineralization, and degree of
ossification of the skull should be
evaluated.
• Interorbital distance should be measured
by using the binocular diameter and
interocular diameter to exclude hyper- or
hypotelorism.

25. Normal Skull
Scaphocephaly Brachycephaly

26. Craniosynostosis seen in
conditions like:
Thanatophoric dysplasia,
Carpenter's syndrome,
Hypophosphatasia,
Crouzon – Aperts.
Wormian bones seen with
Cleidocranial dysplasia,
Osteogenesis imperfecta,
Trisomy 21,
Hypothyroidism,
Progeria.

27. Spine:
• The spine should be carefully imaged to assess
the relative total length and the presence of
curvature to exclude scoliosis.
• Mineralization of vertebral bodies and neural
arches should be evaluated.
• Vertebral height should be subjectively
evaluated for platyspondyly (flattened vertebral
body shape with reduced distance between the
endplates), which is typically seen in
thanatophoric dysplasia.

28. Pelvis:
• The shape of the pelvis can be important in
certain dysplasias, such as limb-pelvic hypoplasia.
• Femoral hypoplasia–unusual face syndrome
(hypoplastic acetabulae, constricted iliac base
with vertical ischial axis, and large obturator
foramina).
• Achondroplasia (flat, rounded iliac bones with
lack of iliac flaring; broad, horizontal superior
acetabular margins; and small sacrosciatic
notches).

29. University of Washington Medical Center Worksheet
while evaluating a patient suspected skeletal dysplasia

31. RADIOGRAPHIC EXAMINATION:
• A complete skeletal survey should be done
in children >6 months.
• In newborns and infants <6 months, at least
–AP and lateral films of the whole spine
–AP films of the hands
–Lateral skull
–Lateral cervical spine flexion and extension

32. Hypoplastic scapulae
in campomelic
dysplasia
Thoraco Lumbar Kyphosis
as seen in Achondroplasia
and Sponyloepithelial
dysplasia

33. Cervical Instability
(Can be seen in every dysplasia except
Achondroplasia)

34. Cervical Instability on MRI

35. Platyspondyly and Thickened, Shortened small
bones commonly seen in Mucopolysaccharidosis

36. Final Diagnosis
• Prenatal/Postnatal onset
• Skeletal features
–short limb/short trunk
–acro, meso or rhizomelia
• Extra skeletal features
• Family history
• Radiographic characteristics
• Laboratory
• Genetic analysis

37. Skeletal dysplasias include more than 380 conditions
leading to abnormally developed bones and
connective tissues

38. Osteogenesis
Imperfecta

39. Synonyms
• Fragilis osseum
• Osteopsathyrosis idiopathica
• Brittle Bone disease
• Glass Bone disease
• Periosteal dysplasia
• Lobstein’s disease
• Vrolik disease
• Porak and Durante’s disease

40. Introduction
• It is a genetic disorder of connective
tissue with clinical features of increased
bone fragility
• It maybe inherited as Autosomal
Dominant or may occur as spontaneous
mutation or rarely inherited as a
homozygous Autosomal Recessive trait

41. Introduction…
• Major clinical features include Skeletal
deformity, Blue sclerae, Fragile opalescent
teeth (Dentinogenesis imperfecta)
• Less severe manifestations include generalised
ligamentous laxity, hernias, easy bruisability
and excessive sweating

42. Normal Collagen Metabolism
• Collagen is a connective tissue protein with a
left handed triple helical structure
• Type I Collagen composed of 2 α1(I) strands
and 1 α2(I) strand
• In fibroblasts the precursors are synthesized in
RER
– Pro α1(I) encoded by COL1A1 on Chr. 17
– Pro α2(I) encoded by COL1A2 on Chr. 7

43. Normal Collagen Metabolism
• 2 Pro α1(I) + 1 Pro α2(I)  type I Procollagen
beginning at the C end and propagating
towards the Amino terminal
• Cross linking - Gly residues; every 3rd position
• Type I Procollagen is secreted from the cells
and processed extracellularly to form Type I
Collagen molecule

44. Collagen Metabolism in OI
• 90% have an identifiable genetically
determined defect, either qualitative or
quantitative, in type I Collagen formation
• Assayed from cultures of fibroblasts from skin
biopsies using electrophoresis

45. Classifications
• Looser (1906) classified into two types
Congenita – Numerous fractures at birth
Tarda – Fractures after perinatal period
• Shapiro subclassified either of these
categories into Type A and Type B

46. • Shapiro’s classified OI into 4 types based on
prognosis for survival and ambulation
OI Congenita A
Fractures in utero or at
birth
Still born or die shortly
after birth
OI Congenita B
Fractures at birth
Long bones are more
tubular and more normal
funnelization in the
metaphysis
OI Tarda A
Onset of fractures prior
to walking
OI Tarda B
First fracture after walking

47. Type I Type II
Most Common, AD
Quantitative defect
Mild form
Distinct blue sclerae
throughout life
Premature arcus senilis
Presenile conductive
Hearing Loss
? AR, Most severe form
Severe qualitative defect
Extreme bone fragility
Death in perinatal period
or early infancy
Crumbled long bones
Marked delay in
ossification of skull bones
Sillence and Dank – 4 types
(Clinical & Genetic characteristics)
IA – Normal Teeth
IB – with Dentinogenesis
imperfecta

48. Type III Type IV
AR or Dominant Negative
Qualitative & quantitative
defect
Severe bone fragility
Multiple fractures,
deformities
Severe growth retardation
Sclerae are bluish at birth,
become less blue with age
and attain normal hue in
adolescence
AD
Qualitative & quantitative
defect
Sclerae are usually
normal hue at birth
Sillence and Dank – 4 types
(Clinical & Genetic characteristics)
IVA – Normal Teeth
IVB – with Dentinogenesis
imperfecta

49. Histopathology
• Bone trabeculae are thin and
lack an organized trabecular
pattern
• The spongiosa is scanty and
intercellular matrix is reduced
• Tetracycline labeled studies
confirm increased bone turnover

50. Clinical Features
(Severe form)
• Multiple fractures from
minimal trauma
• Deformed and short
limbs
• Soft and membranous
skull
• Usually fatal
• Death secondary to IC
hemorrhage or
respiratory insufficiency

51. Clinical Features
(Non Lethal forms)
• Increased fragility of bones (earlier the
fracture, more severe the disease)
• Lower limbs are most commonly affected
• Femur more commonly affected than tibia
• Fractures heal at a normal rate
• Non-union is relatively rare
• Frequency of fractures decline sharply
after adolescence although it may rise
again in postmenopausal women

52. • Bowing of long bones
• Coxa vara
• Short stature
• Hypermobility of joints
• Hypotonic muscles
• Thin and translucent skin, subcutaneous
hemorrhages
• Excessive sweating due to resting
hypermetabolic state
• Heat intolerance
• Metabolic acidosis
• Cardiac arrhythmia

53. Skull
• Forehead broad with prominent
parietal and temporal bones and
overhanging occiput
• Triangular elfin shaped face
• Ears are displaced downwards and
outwards
• The configuration of Skull in OI is
called ‘Helmet head’

54. • Severe spinal deformities (Scoliosis and
Kyphosis)
– Osteoporosis
– Compression fractures
– Ligamentous hyperlaxity
• Scoliosis in 20 – 40% cases, Most commonly
Thoracic scoliosis
• Spondylolisthesis
• Cervical anomalies
Spine

55. • Blue Sclerae
• Saturn’s ring
• Hyperopia
• Arcus juvenilis
• Retinal detachment
• Deafness (40% in Type I,
less in Type IV)
– Conductive
– Otosclerosis or
– Nerve deafness
Eye
Ear

56. • Dentinogenesis
imperfecta (Hereditary
Opalescent Dentine or
Hereditary hypoplasia of
dentine)
• In Type IB and Type IVB
• Enamel normal; teeth
break easily – prone to
caries
• Lower incisors, which
erupt 1st most severely
affected
Teeth

57. Radiologic Features
Severe Form
• Short long bones with thin
cortices
• Wide diaphysis
• Numerous # in various
stages of healing
• Multiple rib # and atrophy
of thoracic cage
• Goldman described
‘popcorn’ calcification in the
metaphysial and epiphysial
area (resolves after
completion of skeletal
maturity)

58. Radiologic Features
Severe Form
Skull
• Mushroom appearance
with thin calvarium
• Delay in ossification
• Wormian bones

59. Radiologic Features
Severe Form
Spine
• Osteoporosis
• Compression #
• Biconcave compressed
vertebral bodies in
between bulging discs
• Kyphoscoliosis

60. Radiologic Features
Milder Forms
• Similar picture of
osteoporosis
• Bowing
• Fractures in various
stages of healing
• Callus typically wispy
but on rare occasions, it
maybe very large and
hyperplastic resembling
Osteosarcoma

61. Hyperplastic Callus & Tumors in OI
Clinical Features
Acute localised
inflammation
Progressive enlargement
of the limb
Investigations
ESR –
Alk Phosphatase –
X-ray – enlarging irregular
callus mass
Treatment
Symptomatic – splinting
? Irradiation
Diphosphonates

62. Final Diagnosis
• Diagnosis is by
–Positive family history
–Clinical and radiologic findings
• Type I Collagen assay
• Antenatal Diagnosis – USG and
Chorionic Villous Sampling

63. Treatment
• No specific treatment
• Rehabilitation – protective bracing and
physiotherapy
• Medical
– Biphosphonates – Pamidronate
– Gene Therapy
– Bone Marrow Transplantation

64. Orthopaedic Treatment
Goal
• Improve function
• Prevent deformity and disability
• Correct deformities
• Monitor for complications

65. Management Of Long Bone Fractures
• Depends on severity and age of the patient
• Fractures should be immobilized only until
symptoms subside
• As a general principle, intramedullary
fixation is preferable to plate and screws
whenever possible because of the stress
risers produced by the later
• Nonunion is rare

66. Management Long Bone Deformity
• Indications for Surgery
–Repeated fractures induced by the deformity
–To apply bracing for either protection against
further fractures or aid in ambulation
• Treatment options
–Closed osteoclasis without internal fixation
–Closed osteoclasis with percutaneous IM
fixation
–Open osteotomy (fragmentation) + IM fixation
- Sofield procedure

67. Management of Spinal deformity
• Patient may not tolerate orthosis
• Spinal fusion for severe progressive
deformity
• Posterior stabilisation with Luque
sublaminar wires or tapes appears to
be ideally suited for instrumentation
in management of difficult cases

68. Blount’s Disease

69. Introduction
• Tibia vara is defined as the growth retardation
of the medial aspect of the proximal tibial
epiphysis usually resulting in progressive bow
leg. Classified into three groups as
– Infantile < 3years
– Juvenile 4 – 10 years
– Adolescent > 10 years
• Blount classified Tibia vara as
– Infantile < 8 years (known as Blount’s Disease)
– Adolescent > 8 years

70. Blount’s Disease
• Erlacher (1922)
• Blount (1937)
• Synonyms
–Infantile Tibia vara
–Erlacher’s disease
–Blount-Barber syndrome
–Deformative osteochondrosis of the tibia
–Nonrachitic bowleg in children
–Osteochondritis deformans tibiae
–Subepiphyseal osteochondropathy

71. Etiology
• Familial: Autosomal Dominant inheritance
• Developmental
• Multifactorial:
–Infection
–Trauma
–AVN
–Latent form of rickets
• Others: early weight bearing, obesity

72. Histology
• The physeal cell columns become irregular
and normal endochondral ossification is
disrupted in the medial aspect of
metaphysis and physis
• Islands of nearly acellular fibrocartilage
• Islands of densely packed cartilage cells
with greater hypertrophy than expected
from their position in the growth plate
• Large clusters of capillary vessels

73. Clinical Features
• Similar to physiological genu varum with 2
major differences
–Usually obese and start walking early
–Clinically apparent lateral thrust to the knee
during the stance phase
• Usually bilateral and symmetrical (60%) and
varus deformity increases progressively
• Varus, internal tibial torsion and genu
recurvatum, plano valgus develops
secondarily
• Siffert – Katz sign

74. Radiological Features
• Varus angulation at epiphysio-
metaphyseal junction
• Widened and irregular physeal
line medially
• Medially sloped and irregularly
ossified epiphysis, sometimes
triangular
• Epiphysis short thin and wedged
• Prominent beaking of the medial
metaphysis, with lucent cartilage
islands within the beak
• Lateral subluxation of the
proximal tibia

75. Radiological Features
• According to Smith,
medial metaphysial
fragmentation is
pathognomonic for
the development of
a progressive tibia
vara

76. Tibio Femoral Angle Metaphysio Diaphysial angle
(Levin and Drennen)
MD
angle

77. Other Imaging Modalities
• MRI: Able to demonstrate
the extent of the ossified
and cartilaginous
epiphysis along with any
physeal anatomical
disruption
• Arthrography: Dalinka
demonstrated
hypertrophy of the medial
meniscus and the
unossified cartilage of the
medial tibial plateau

78. CT Scan
• Greene listed the following criteria for
preoperative CT to determine if a bony
bar is present
–Age > 5 years
–Medial physeal slope 50 – 70 degrees
–Stage IV X-ray findings
–Weight more than 95th percentile
–Black female who meet the following
criteria

79. Langenskiold classification (1952)
• I - Irregular metaphyseal ossification combined with medial and
distal protrusion of the metaphysis
• II, III, IV - Evolves from a mild depression of the medial metaphysis
to a step-off of the medial metaphysis
• V - Increased slope of medial articular surface and a cleft
separating the medial and lateral epicondyle
• VI - Bony bridge across the physis
Depending on degree of metaphysial and epiphysial
changes on radiograph

80. Prognosis Based On Langenkiold
classification
• Better prognosis in earlier stages
–I & II can predictably have full restoration
with single osteotomy and bracing;
treatment must be completed before 4
years
–III maybe restored
–IV – VI requires complex reconstruction and
physeal procedures with guarded outcome
at best

81. Treatment
• Untreated infantile tibia vara
generally results in progressive varus
deformity, producing joint deformity
and growth retardation.
• Treatment choices and prognosis
depend greatly on the age of the
patient at the time of diagnosis.

82. Orthotics
• Recommended for patients < 3 years of age and
<stage II disease
• Rainey et al recommended KAFO that produced a
valgus force by three point pressure
• Risk for failure included ligamentous instability,
patient weight above 90th percentile and late
initiation of bracing
• Elastic Blount brace, a medial upright design with
drop lock knee hinge that can be locked to
increase the effectiveness of valgus pressure
during weight bearing

83. Corrective Osteotomy
• Beatey et al recommended valgus
osteotomies of proximal tibia and fibula
with mild overcorrection in young
children
• Early osteotomy produced best results
chance of recurrence increased with
increasing age

84. • Greene described Chevron osteotomy in
which opening and closing wedges can
be made so that the limb length
deformity present in moderate to severe
tibia vara will not be increased.
• He described a crescent shaped
osteotomy using one half lateral closing
wedge and using the graft medially in an
opening wedge to maintain length.

85. • In children older than 9 years
with more severe involvement,
osteotomy alone, with bony bar
resection, or with epiphysiodesis
of the lateral tibial and fibular
physes may be indicated.

86. Achondroplasia

87. • Achondroplasia is a type of short-
limbed dwarfism
• It occurs when the process by which
cartilage is converted to bone, or
ossification, is stunted
• This is most apparent in the long
bones of the arms and legs
• Incidence is 1 in 25,000 live births

88. Etiology
• Autosomal dominant
inheritance
• Due to mutations of the
FGFR3 gene on the short
arm of chromosome 4
• This gene regulates bone
development, so when
affected, it causes
malfunctions in bone
growth

89. Clinical Presentation
• Short arms and legs:
particularly the upper arms
and thighs
• Enlarged head (macrocephaly)
• Prominent forehead
• Short fingers: the middle and
ring fingers may diverge,
giving the hand a three-
pronged (trident) appearance

90. • Sleep apnea
• Persistent ear infections
• Exaggerated Lumbar Lordosis
• Bowed legs
• Mid-face hypoplasia
• Hypotonia: low and weak muscle tone
• Delays in walking and other motor skills
• Back pain
• Obesity
• Bowed legs
• Limited range of motion at the elbows

91. Diagnosis
• Characteristic clinical findings
• X-ray findings
• Genetic analysis

92. Treatment
• There is no specific or permanent treatment.
• Measures to avoid obesity are taken.
• To correct obstructive sleep apnea, a surgical
opening in the airway, or tracheostomy, can be
performed.
• With patients with problems such as
hyperreflexia, clonus, or central hypopnea:
suboccipital decompression, which decreases
pressure on the brain can be done.
• Growth hormones and/or surgery may be able to
lengthen limbs, but only up to a certain limit.

93. Marfan’s Syndrome

94. Description
•Heritable disorder of the
connective tissue
•Connective tissue affects:
•Growth and development
•Cushioning of joints
•Vital organs
•1 in 5,000 people in US
have disorder

95. Symptoms
• Affects many body systems including:
– Skeleton
– Eyes
– Heart and Blood Vessels
– Nervous System
– Lungs
– Skin

96. Skeleton
• Tall and slender
• Disproportionately long appendages
• Indented or protruding sternum
• Arched palate, overcrowded teeth, receding
mandible
• Curvature of spine

97. Eyes
• Off-center or dislocated
lenses
• Nearsightedness (Myopia)
• Development of cataracts at
a younger age (30s to 50s)
• Retinal detachment
• Stretch marks
– Shoulders, hips, lower back
• Increased risk for abdominal hernias
Skin

98. Heart and Blood vessels
• Weakened middle layer of
aortic wall
– Stretched aortic valve leaflets
– Aneurysm may form
• Aortic regurgitation
– Left ventricle must compensate
– Chest pain, heart failure
• Tears in inner and middle
aortic layers
– Middle layer separates
– New channels for blood flow

99. Nervous System
• Stretching and enlargement of dura membrane
– Pushes on and wears down vertebrae
– Can protrude through vertebral column and into abdomen
– Dural cysts
• Increased susceptibility to learning disabilities

100. Lungs
• Diminished alveoli elasticity
• Susceptibility to asthma,
bronchitis, pneumonia
– In rare cases, develop
emphysema
• 5% experience spontaneous
lung collapse
• Sleep disordered breathing
– Snoring most common
– Caused by partial obstruction of
airway by connective tissue

101. Basic Genetic Information
• Autosomal Dominant
• Dominant Negative Mutation – the altered
gene product antagonizes the product of the
normal gene
• Haploinsufficiency – when a diploid organism
has only one functional copy of a gene, the
other copy being mutated
• Affects FBN-1 Gene

102. FBN-1 Gene
• Located on chromosome 15
• Codes instructions for the
creation of protein Fibrillin 1
• Marfan’s is caused by over
500 different mutations on
FBN1
• 60% mutations are change in
one protein building block.
• 40% mutations produce
small protein that can’t
function

103. Fibrillin 1 protein
• Connect with other Fibrillin 1 proteins to make
microfibrils, which become connective tissue.
• Microfibrils mainly trap transforming growth factor-
beta (TGF-beta) and keeps them inactive.

104. Defective Fibrillin 1 Protein
• Amount of fibrillin 1 protein produced by cells
is reduced
• Structure and stability of protein is affected
• Transport of fibrillin 1 protein out of the cell is
impaired
• Amount of fibrillin 1 reduced means
decreased microfibril production
• Less microfibril leads to more active TGF-beta,
which leads to Marfan’s symptoms

105. Testing and Diagnosis
• Genetic analysis:
–Types
•Complete bi-directional DNA
sequencing
•FBN1 gene sequencing
•TGFBR gene sequencing
•Familial mutation test

106. • Other
–Imaging tests
• Chest x-ray
• MRI
–Symptoms checklist
• Family history + 2
affected body systems
• At least 3 affected
body systems

107. • Index case:
Major criteria in 2 different organ systems
AND involvement of a third organ system.
Relative of index case:
1 major criterion in family history
AND 1 major criterion in an organ system
AND involvement in second organ system.
SKELETAL
Major (Presence of at least 4 of the following manifestations)
__ pectus carinatum
__ pectus excavatum requiring surgery
__ reduced upper to lower segment ratio (Note 1)
OR arm span to height ratio >1.05
Height ____ Arm span ____ Upper segment ____ Lower segment ____
__ wrist (Note 2) and thumb (Note 3) signs
__ scoliosis of >20° or spondylolisthesis
__ reduced extension at the elbows (<170°)
__ medial displacement of the medial malleolus causing pes planus
__ protrusio acetabulae of any degree (ascertained on radiographs)
Minor
__ pectus excavatum of moderate severity
__ joint hypermobility
__ high arched palate with crowding of teeth
__ facial appearance
__ dolichocephaly,
__ malar hypoplasia,
__ enophthalmos,
__ retrognathia,
__ down-slanting palpebral fissures
Diagnostic Checklist
OCULAR
Major
__ ectopia lentis
Minor
__ flat cornea
__ increased axial length of the globe
__ hypoplastic iris OR hypoplastic ciliary muscle causing decreased miosis
CARDIOVASCULAR
Major
__ dilatation of the ascending aorta with or without aortic regurgitation
and involving at least the sinuses of Valsalva
__ dissection of the ascending aorta
Minor
__ mitral valve prolapse with or without mitral valve regurgitation
__ dilatation of the main pulmonary artery, in the absence of valvular or
peripheral pulmonic stenosis below the age of 40 years
__ calcification of the mitral annulus below the age of 40 years
__ dilatation or dissection of the descending thoracic or abdominal aorta
below age of 50 years
PULMONARY
Minor (only)
__ spontaneous pneumothorax
__ apical blebs
SKIN AND INTEGUMENT
Minor (only)
__ striae atrophicae
__ recurrent or incisional hernia
DURA
Major
__ lumbosacral dural ectasia by CT or MRI
FAMILY/GENETIC HISTORY
Major
__ first degree relative who independantly meets the diagnostic criterian.
__ presence of mutation in FBN1 known to cause Marfan syndrome
__ presence of haplotype around FBN1 inherited by descent and
unequivocally
associated with diagnosed Marfan syndrome in the family

108. • Positive Steinburg
Thumb Sign
 Positive Walker
Wrist Sign

109. Treatment
• Require a multidisciplinary team
• Symptoms, not disorder, must be
treated
• Yearly echocardiograms
• Emotional support
• Healthy Diet

110. Heart
• Enlargement of the aorta
– Aortic Dissection
• Aortic Dilation
– Aortic Valve regurgitation
– Mitral valve prolapse
• Medications
– Lower blood pressure
– Angiotensin receptor blockers
– Beta blockers
• Regular Echocardiograms

111. Skeleton
• Physiotherapy
• Pain Clinics
–Loose joints
• Bracing
–Back
–Ankle
• Surgery
–Pectus excavatum

112. Physical Activity
• Avoid contact and strenuous sports
because of the risk of damaging the
aorta and injuring the eyes
• Individual restrictions based on
severity and discussed with
physician

113. Apert’s Syndrome

114. • Described first by a French physician in
1906
• Also known as
ACROCEPHALOSYNDACTYLIA
• A genetic disorder with Autosomal
Recessive inheritance
• Affected gene is called FGFR2 (Fibroblast
Growth Factor Receptor 2)
• Locus on chromosome is 10q26

115. • All groups are affected
–Most prevalent in Asians;
• Incidence in Asians is 22.3 per million
births
• Age of onset is at birth
• Diagnosed at birth itself due to
peculiar features like syndactyly and
shape of the skull

116. Clinical Signs
• Early closure of sutures between the
bones in the skull
• Frequent ear infections
• Fusion or severe webbing of the 2nd,
3rd, and 4th fingers
–“mitten hands”
• Hearing loss
• Large or late-closing soft spot on a baby’s
skull
• Possible, slow intellectual development

118. • Severe under-development of the
mid-face
• Skeletal (limb) abnormalities
• Short height
• Webbing or fusion of the toes
• Prominent or bulging eyes

119. Frequently Associated Conditions
• Dextrorotation
• Pulmonary Atresia
• Patent Ductus
Arteriosus (PDA)
• Tracheoesophageal
Fistula
• Pyloric stenosis
• Polycystic Kidneys
• Ear infections
• Sleep Apnea
• Severe acne
• Hydrocephalus
• Bicornate uterus

120. Treatment
-Separation of the abnormally fused skull
bones to allow for the growth of the head
Done in infancy
-Correction of midface hypoplasia using
the Ilizarov procedure
Opens up the bones of the middle of the
face and stimulates them to grow
Done between ages 6-11
-Separation of fingers and toes

121. Correction of midface hypoplasia
using the Ilizarov procedure

122. Osteopetrosis

123. • Also known as Marble bone
disease and Alber Schonberg’s
disease
• Developmental abnormality in
which the bones throughout the
body become increasingly dense
and brittle

124. Etiology
• Defective Carbonic anhydrase function
• Lack of alkaline environment for
osteoclast function
• Defective osteoclast function
• Continued new bone deposition with no
resorption
• Bones are hard as marble or can be
brittle like a chalk and are grey or white
on cut section

125. • The medullary cavity is obliterated
and deficient in bone marrow
leading to pancytopenia and reduced
immunity.
• Bony encroachment on cranial
foramina can produce optic atrophy
deafness and facial paralysis.

126. Types
• Infantile osteopetrosis:
– Autosomal recessive
– Severe form
– Poor prognosis
– Usually patient dies by 2 years of age
• Benign adult osteopetrosis:
– Autosomal dominant
– Less severe form (usually detected
incidentally), Good prognosis

127. Clinical Features
• Shape of head (Box like appearance)
• Hepatosplenomegaly
• Lymphadenopathy
• Optic atrophy, deafness or facial paralysis
in cases with stenosis of cranial foramen
• Anaemia
• Pancytopenia
• Frequent infections and osteomyelitis

128. Radiological features
• Increased density of all
bones with decreased
remodelling.
• Widened shafts,
decreased marrow space
in long bones due to
increased cortical
thickness.
• Base of skull is thickened
with narrowed cranial
foramen.

130. • Paranasal sinuses : poorly
pneumatized (ethmoid
sinuses least severely
affected)
• Calvarium : high-
attenuation inner table, a
broad, low-attenuation
diploic space, and a less
high-attenuation outer
table

131. Blood Routine
• Anaemia
• Pancytopenia
• Most patients have normal levels of serum
Calcium, Phosphate and Alkaline
Phosphatase.
• Recessive disease may have Hypocalcemia
during infancy

132. Treatment
• Symptomatic treatment for pain relief
• Bone marrow transplantation for
malignant/ lethal disease is the only
treatment option

133. THANK YOU