Connective tissue disorders can affect the supporting tissues of the body. This document discusses Ehlers-Danlos syndrome and Marfan syndrome as two examples. Ehlers-Danlos syndrome is a hereditary disorder characterized by joint hypermobility and skin elasticity due to abnormalities in collagen. Marfan syndrome is also hereditary and affects connective tissues, causing skeletal abnormalities, vision and heart problems due to a genetic mutation affecting fibrillin. Both disorders demonstrate the importance of connective tissues and can be diagnosed through their distinct clinical manifestations and genetic testing.

1. CONNECTIVE TISSUE DISORDERS
Lalisa M. ( MD, OSR)
SPHMMC, AaBET Hospital
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2. CONTENT
 Introduction
 Ehler danlos syndrome
 Marfan syndrome
 Scurvy
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3. INTRODUCTION
♦CONNECTIVE TISSUE
 Connective tissue (CT) is a tissue that connects, supports, binds, or
separates other tissues or organs; forming a framework to support
body tissues and organs.
 CT is one of the four basic types of human tissue along with epithelial
tissue; muscle tissue and nervous tissue.
 CT is made up of cells and extracellular matrix.
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4. INTRODUCTION
 CT is made up of :-
- Fibrous components ( collagen and elastin) (
- GAGs
- Proteoglycans
CT is classified into two:-
- Loose irregular CT
- Dense irregular CT
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5. INTRODUCTION
 Specialized CT includes:-
- Dense regular CT ( found in tendons and ligaments)
- Cartilage
- Adipose tissue
- Lymphatic tissue
- Blood
- Bone
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6. INTRODUCTION
♦CONNECTIVE TISSUE DISORDERS
 A group of disorders that affect the supporting tissue of our body
 > 200 disorders that affect CT
 Many of the disorders result from abnormal immune system activity
with inflammation in tissues.
 Has overlapping clinical features
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7. INTRODUCTION
 Categorization of connective tissue disorders:
1) Heritable connective tissue disorders
- Many of them rare; some of the more common ones:-
- Ehlers-Danlos syndrome (EDS)
- Epidermolysis bullosa
- Marfan syndrome
- Osteogenesis imperfecta
- Stickler syndrome
- Alport syndrome
- Beals syndrome / Congenital contractural arachnodactyly
- Loeys-Dietz syndrome
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8. 2) Autoimmune connective tissue disorders
- Here immune system produces antibodies that target the body’s own
tissue for attack Examples:-
- Dermatomyositis and polymyositis
- Rheumatoid arthritis
- Scleroderma
- Sjogren’s syndrome
- SLE
- Vasculitis
- Mixed connective tissue diseases
3) Other connective tissue disorders
- Peyronie’s disease
- Scurvy
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9. EHLERS-DANLOS SYNDROME
 A group of more than 10 different inherited disorders characterized by
abnormalities of collagen metabolism that result in varying degrees of
 joint laxity
 skin hyperelasticity
 tissue fragility.
 Ehlers, in 1901, described patients with loose joints and subcutaneous
hemorrhages.
 Danlos, in 1908, added subcutaneous tumors that may
develop at pressure points to the description.
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10. CAUSES
 vary significantly
 Collagen disorganization and/or abnormal bundle size is correlated with
clinical evidence in joints; skin and blood vessels
 Mutation with specific molecular defect of 1,3 & 5 collagen
 Mutations in the TNXB gene, result in the reduction of tenascin X
 >90 % - Autosomal dominant inheritance, autosomal recessive, or X-
linked
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11. EPIDEMIOLOGY
 Prevalence: 1 case in ~ 400 000 people
 No racial predominance exist
 Almost equal sex-related prevalences
 Usually diagnosed in young adults
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12. CLINICAL FEATURES
 Skin manifestations
- Common to almost all group is a unique appearance of the skin
 vary from mild laxity to extreme laxity with delayed relaxation
 extremely thin skin with poor wound healing; use of sutures usually a
problem.
 Molluscoid pseudotumors at sites of friction, such as the elbows, heels, and
knees.
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14.  Other features are different for the variants:-
 Joint hypermobility & hyperextensibility>> hx of recurrent dislocations
Shoulder dislocation is often the initial sign of EDS.
 Bleeding gums, easy brusiability with persistent hyperpigmentation (
 Scoliosis, spondylolisthesis, and atlantoaxial instability
 Vascular and intestinal ruptures
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17. OLDER CLASSIFICATION OF EDS
 Type 1- Gravis form
- affects 43% of patients
- autosomal dominant inheritance
- kyphoscoliosis; hallus valgus; flat feet and genu recurvatum
common in addition to skin and joint abnomalities
- prematurity with rupture of the fetal membranes is specific to this
type
 Type 2- Mitis form
- affects 35% of patients
- AD inheritance
- xed by mild appearance of the same features of type 1
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18.  Type 3- Benign familiar hypermobile form
- affects 10% of patients
- AD inheritance
- minimal or no skin changes; but they do have a striking
hyperextesibility in many joints
 Type 4- Ecchymotic or arterial form
- affects 6% of patients
- Autosomal recessive inheritance or sometimes AD pattern
- unique translucent skin with bruises and purpuric lesions
- sudden death can occur after visceral perforation or after rupture
of a large vessel; most commonly an abdominal or splenic vessel
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19.  Type 5- X-linked form
- affects 5% of patients
- inherited in X-linked recessive pattern
- highly extensible skin and orthopaedic abnormalities are common
 Type 6- Ocular form
- affects 2% of patients
- inherited in autosomal recessive pattern
- severely affected group
- ocular fragility can cause retinal hemorrhage and detachment
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20.  Type 7- Arthrochalasis multiplex congenita
- affects 3% of patients
- Autosomal recessive inheritance or AD pattern
- joint hyperextensibility; spontaneous joint dislocation usually with
rapid reduction is common
Type 8- Periodontal form
- rare; with AD inheritance
- have gingival periodontal inflammation ( gingival resorption and
permanent loss of the teeth are common by the time patient is aged 30
years)
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21.  Type 9 – X-linked cutis laxa
 - rare & inherited in x-linked recessive pattern
 - have xtic bilateral bony prominences on the occiput
 - chronic diarrhea and orthostatic hypotension are unique findings
 Type 10 – fibronectin deficiency
 Type 11- benign hypermobile joint syndrome
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22. 1997 CLASSIFICATION
 EDS is clinically heterogeneous and has been classically divided into the
following types with underlying collagen abnormality being different for
each type:
- Classical ___ formerly types 1 & 2
- Hypermobile __ formerly type 3
- Vascular__ formerly type 4
- Kyphoscoliotic __ formerly type 6
- Arthrochalasis __ formerly type 7 ( proA1 or proA2 chain deficiency
of collagen type 1)
- Dermatosparaxis__ formerly type 7 ( deficiency of procollagen N-
terminal peptidase)
- Other ___ formerly types 5; 8; 9; 10; 11
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23. CLASSIFICATION
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24. 2017 EDS INTERNATIONAL CLASSIFICATION
 cEDS- Classical Ehler-Danlos syndrome
 clEDS- Classical-like EDS
 cvEDS- Cardiac-valvular EDS
 vEDS- Vascular EDS
 hEDS- Hypermobile EDS
 aEDS- Arthrochalasia EDS
 dEDS- Dermatosparaxis EDS
 kEDS- Kyphoscoliotic EDS
 BCS- Brittle cornea syndrome
 spEDS- Spodylodysplastic EDS
 mcEDS- Musculocontractural EDS
 pEDS- Periodontal EDS
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25. COMPLICATIONS OF EDS
 Prone to trauma
 Pregnancy related complications
 Bleeding risks during surgery
DIFFERENTIAL DIAGNOSIS
 Cutis Laxa ( Elastolysis)
 Loeys-Dietz syndrome
 Pseudoxanthoma Elasticum
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26. WORKUP
 Radiographs may show calcification of subcutaneous nodules
 Skin biopsy- histologically dermal collagen fibers are disorganized
with whorled appearance
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27. TREATMENT
 No specific treatments to correct the biochemical defects responsible
for the collagen abnormalities.
 One isolated report showed that patients with type 4 disease benefited
from oral vitamin C at 4g/d.
 Joint dislocations - treated with standard immobilization methods
 Extreme caution is mandatory in any surgical maneuver
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28. TREATMENT. . .
 Wound dehiscence and healing complications are common.
 Careful positioning is required to prevent injury, subluxation, or
dislocation.
 Posterior spinal fusion with stable instrumentation for kyphoscoliosis.
 The management of vascular and visceral ruptures
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29. MARFAN SYNDROME
 One of the most common inherited disorders of connective tissue
associated with:-
 Long limbs
 Skeletal abnormalities
 Cardiovascular abnormalities
 Ocular abnormalities
 1st described by Antonin Bernand Jean Marfan (1896). He was a
French pediatrician.
 Incidence of 1 in 3000 to 5000 individuals
 No ethnic or gender predilection known
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31. MFS...
 Inherited almost exclusively in an autosomal dominant manner and is
caused by mutations in the fibrillin gene. Rare case reports of
recessive FBN1 mutations is also described.
 In less than 10% of cases with typical Marfan phenotype; no mutation
in FBN1 is identified. In some of these individuals; an inactivating
mutation in a gene encoding for TGFBR may be resposible.
 25- 30%- sporadic.
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32. FBN1
 Located at chromosome 15
 Code for FBN1 protein, a large glycoprotein closely associated with
elastin.
 It is an important component of both elastic and nonelastic connective
tissues.
 In addition to their presence in the aortic media and suspensory
ligaments of the lens, fibrillin microfibrils are found in skin, tendon,
cartilage, and periosteum.
 Abnormal or absent fibrillin alters tissue elasticity.
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33. MFS PATHOGENESIS
 How FBN1 or TGFBR mutations lead to disease is not well
understood is not well understood at molecular level. Among the
proposed mechanisms are alterations in:-
♦ Calcium binding to EGF-like domains ( supported by the loci of
some FBN1 mutations)
♦ Increased bioavailability of transforming growth factor (TGF)-
beta.
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34. CLINICAL MANIFESTATIONS OF MFS
 Aortic disease
- aneurysmal dilatation; aortic regurgitation and dissection is the main
cause of morbidity and mortality in the MFS.
- the aorta in MFS tends tend to be stiffer and less distensible than in
controls
- dilatation of the aorta is found in approximately 50% of children with
MFS and progress with time
- all aortic roots with diameter ≥40 mm are considered dilated
Cardiac disease
- MVP is frequently identified in patients with MFS
- the frequency of MVP in MFS increases with age and is greater in
women
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35. CLINICAL MANIFESTATIONS OF MFS
 Skeletal findings
- individuals with MFS have excess linear growth of long bones and
joint laxity
- the individuals are taller than predicted by their genetic background;
which is generally; but not necessarily; tall compared to general
population standards
- Patients with Marfan syndrome are typically tall—usually
attaining a height greater than 6 feet in adult life.
- Paradoxically, some individuals with MFS have reduced joint
mobility, particularly of the elbow and digits.
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38. SKELETAL FINDINGS . . .
 Arachnodactyly — long thin spider-like digits
 Thumb sign /Steinberg sign
 Wrist sign
 Pectus deformity — Pectus carinatum or pectus excavatum
 Hindfoot valgus ± pes planus
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40. ARACHNODACTYLY...
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41. SKELETAL FINDINGS . . .
 Abnormal US/LS and arm span/height — Individuals with MFS
have disproportionately long extremities in comparison to the length of
the trunk (dolichostenomelia), so the upper segment to lower segment
(US/LS) ratio is decreased and the arm span to height ratio is
increased.
 The crossleg sign is the ability to touch the floor with the foot of the
crossing-over leg.
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44. SKELETAL FINDINGS . . .
 Scoliosis and kyphosis — scoliosis is usually the first to be
diagnosed. Presence of either of the following findings is diagnostic
for scoliosis:
 With the patient bending forward, observation of a vertical difference of ≥1.5
cm between the ribs of the left and right hemithorax.
 A Cobb’s angle of at least 20 degrees.
 Protrusio acetabuli — Acetabular protrusion can be diagnosed by
plain x-ray, CT or MRI. On an anterior-posterior (AP) pelvic film,
medial protrusion of the acetabulum ≥3 mm beyond the ilio-ischial
(Kohler) line is diagnostic.
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46. CLINICAL MANIFESTATIONS OF MFS···
 Facial features — inclodes: dolichocephaly [reduced cephalic index
or head width/length ratio], enophthalmos, downslanting palpebral
fissures, malar hypoplasia, retrognathia
 Ocular abnormalities —
 Ectopia lentis occurs in 50 to 80 percent with MFS.
 Patients with MFS develop secondary myopia due to increased axis globe
length.
 Other ocular findings in MFS include flat cornea , retinal detachment,
glaucoma, and early cataract formation.
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48. CLINICAL MANIFESTATIONS OF MFS···
 Dural ectasia — Dural ectasia results from enlargement of the spinal
canal owing to progressive ectasia of dura and neural foramina and to
erosion of vertebral bone.
 Pneumothorax
 Skin striae
 Other — Recurrent or incisional herniae, joint hypermobility and high
arched palate may occur but are not included in the systemic score
since these clinical features are considered nonspecific.
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49. REVISED GHENT CRITERIA FOR DIAGNOSIS OF MFS
 In the absence of family history of MFS, the presence of one of any of the
following criteria is diagnostic for MFS:
 Aortic criterion (aortic diameter Z≥2 or aortic root dissection) and ectopia lentis*
 Aortic criterion (aortic diameter Z≥2 or aortic root dissection) and a causal FBN1 mutation
 Aortic criterion (aortic diameter Z≥2 or aortic root dissection) and a systemic score ≥7 *
 Ectopia lentis and a causal FBN1 mutation that has been identified in an individual with
aortic aneurysm
 In the presence of family history of MFS (as defined by the above criteria), the
presence of one of any of the following criteria is diagnostic for MFS:
 Ectopia lentis
 Systemic score ≥7 points*
 Aortic criterion (aortic diameter Z≥2 above 20 years old, Z≥3 below 20 years, or aortic root
dissection)*
 For criteria with an asterisk (*), the diagnosis of MFS can be made only in the
absence of discriminating features of Shprintzen-Goldberg syndrome (SGS),
Loeys-Dietz syndrome (LDS), or vascular Ehlers-Danlos syndrome (vEDS) and
after TGFBR1/2, collagen biochemistry, or COL3A1 testing if indicated.
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50. REVISED GHENT CRITERIA
 Systemic score — The revised Ghent nosology includes the following scoring system for
systemic features:
 Wrist AND thumb sign: 3 points (wrist OR thumb sign: 1 point)
 Pectus carinatum deformity: 2 (pectus excavatum or chest asymmetry: 1 point)
 Hindfoot deformity: 2 points (plain pes planus:1 point)
 Pneumothorax: 2 points
 Dural ectasia: 2 points
 Protrusio acetabuli: 2 points
 Reduced upper segment/lower segment ratio (US/LS) AND increased arm span/height AND no
severe scoliosis: 1 point
 Scoliosis or thoracolumbar kyphosis: 1 point
 Reduced elbow extension (≤170 degrees with full extension): 1 point
 Facial features (at least 3 of the following 5 features: dolichocephaly [reduced cephalic index or head
width/length ratio], enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia): 1
point
 Skin striae: 1 point
 Myopia >3 diopters: 1 point
 Mitral valve prolapse (all types): 1 point
 A systemic score ≥7 indicates systemic involvement.
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51. DIAGNOSTIC CRITERIA
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52. WORKUP
 Molecular genetic test can assist but not diagnostic
 Standard radiography
- Hand radiographs – arachnodactly shown by metacarpal index
- Spine radiographs- kyphoscoliosis
- Pelvic radiograph– may show protrusio acetabuli
- CXR – may show pectus excavatum or carinatum
- Foot x-ray – pes planovalgus
 CT – may detect subtle protrusio acetabuli
 MRI– may detect subtle protrusio acetabuli and dural ectasia
 Echocardiography and ECG– detect cardiac abnormality
 Slit-lamp ocular examination– lens and retinal abnormality
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54. MANAGEMENT
 No specific procedure to cure MFS but systemic-specific treatment
 Cardiovascular
 restriction of vigorous physical exercise
 advised to avoid contact sports, exercise to exhaustion, and especially isometric
activities which entail the Valsalva maneuver
 routine and noninvasive monitoring of aortic size
 elective surgical repair of the aorta.
 Elective replacement of aortic root disease before critical enlargement is
preferable to emergency repair for marked dilatation or dissection.
 Recommend elective operation for patients with MFS at an external diameter of
≥50 mm to avoid acute dissection or rupture
 Two approaches are used for aortic root replacement: a composite valve graft
and valve-sparing aortic root replacement.
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55. CARDIOVASCULAR...
 Beta blockers
 decrease myocardial contractility and pulse pressure ,improve the elastic
properties of the aorta particularly in patients with an aortic root diameter <40
mm
 beta blockers should be administered to all patients with MFS and aortic
aneurysm to reduce the rate of aortic dilatation unless contraindicated
 Patients who do not tolerate use of beta blocker may benefit from an
angiotensin receptor blocker (preferably losartan ), an angiotensin converting
enzyme inhibitor, or a calcium channel blocker (preferably verapamil ).
 NB: Ay evidence of aortic dilatation must be treated medically or
surgically before any spinal reconstruction is attempted
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56. CARDIOVASCULAR...
 Mitral valve repair or replacement is recommended for severe mitral
regurgitation with associated symptoms or progressive left ventricular
dilatation or systolic dysfunction.
 Obstetric complications appear to be increased in women with MFS.
There are high rate of premature deliveries (15 percent), mainly due to
preterm premature rupture of membranes and cervical insufficiency, and
a markedly increased combined rate of fetal and neonatal mortality (7
percent).
 Cesarean delivery is preferred in patients with an aortic diameter >40
mm, aortic dissection, severe aortic regurgitation or heart failure.
 Women with MFS should receive pregnancy counseling. They should
understand that aortic rupture or dissection can occur during pregnancy
at any root size.
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57. CONT..
 Spine
- Scoliosis- three dimensional deformity in curvature of spine
- is the most common major skeletal deformity in patients with MFS
- more than 60% of patients with MS has some form of scoliosis; but few needs treatment
depending on the degree of deformity
- The double major right thoracic-left lumbar curve is the most common type among type
among patients with MFS; whereas a single type is seen in idiopathic type In contrast; in
MFS the curve is progressive and painful
- Tx:- - Observation- serial radiographs every 3-4bmonths is recommended for curves
less than 25 degrees
- Bracing ( works if growth is remaining ; curves 25-40 degrees and slow
progressing ones); controversial and many believe the curve progress regardless of
bracing and require operative intervention Mainly used as a bridge to future surgery
- Surgery– for curves greater than 40-50 degrees or with abnormal sagittal
curvature
- Posterior spinal fusion and segmental spinal instrumentation; along with
autogenous bone grafting
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58. CONT..
 Ophthalmologic evaluation is suggested annually due to propensity to
lens subluxation (ectopia lentis), cataract, glaucoma, and retinal
detachment.
 Eye care includes vision correction for myopia and photocoagulation for
retinal tears and detachment. Early monitoring and aggressive refraction
is recommended for children with MFS to prevent amblyopia.
 A dislocated lens should not be removed surgically unless more
conservative means of correcting vision are ineffective. Indications for
surgical lens extraction include lens opacity with poor visual function,
refractive error not amenable to optical correction, impending complete
luxation, and lens induced glaucoma or uveitis.
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59. MANAGEMENT...
 Ligamentous laxity
- fibrillin abnormality leading to abnormally stretching ligaments
- mostly doesn’t cause problem; and sometimes considered as a gift
- may manifest as severe pes planovalgus or joint dislocations, especially of the
patellofemoral joint. There may be a history of ankle sprains secondary to
ligamentous laxity. In general, treatment of these conditions should be as
conservative as possible because obtaining and maintaining joint stability can be
difficult in these patients.
 Feet
-Flat foot deformity– due to prolonged ligamentous laxity
- mostly not paiful; treated if painful with orthotics & rarely surgery
 Acetabular protrusio-- observation unless severe symptoms develop
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60. SCURVY
 It is clinical manifestation of vitamin C deficiency
 The disease is rare and is now most commonly seen in patients following
extreme diets, such as patients with anorexia nervosa.
 Historically, scurvy was described in sailors whose diets lacked vitamin C
during long sea voyages.
 Ascorbic acid synthesis is not done in the body and relies on external
sources
 Vitamin C is necessary for the hydroxylation of lysine and proline to
hydroxylysine and hydroxyproline, two amino acids crucial to the proper
cross-linking of the triple helix of collagen. The result is primitive collagen
formation throughout the body, including the blood vessels, which
predisposes to hemorrhage
 Leads to decreased collagen formation and collagen formed is of poor quality
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62. SCURVY. . .
 Scurvy develops after 6 to 12 months of dietary deprivation
of vitamin C.
 Osteoblasts become dysfunctional, with failure to produce osteoid
tissue and form new bone.
 New bone formation is prevented and old bone becomes brittle
 Hemorrhage tendency due to fragility of capillary walls
-bleeding subperiosteally and marrow particularly in metaphysis
adjacent to actively growing epiphysis
 Interferes with growth of osteoblasts into calcified bone
 Failure of conversion of calcified cartilage into bone

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63. CLINICAL FEATURES OF SCURVY
 Loss of appetite, irritability, and failure to thrive.
 Pseudoparalysis– extremeties held immobile due to muscle spasm
 The limbs become exquisitely tender, so much so that the infant screams on
movement of the affected areas. The child lies still in the frog-leg
position to minimize pain, a posture called pseudoparalysis.
 Subperiosteal h’ge- palpable soft & extremely tender swelling fixed to
bone
 Subperiosteal hemorrhage is a distinctive sign that usually occurs in the distal
femur and tibia and proximal humerus.
 Bluish tender bleeding and swollen gum
 Hemorrhage may also develop in the soft tissues, including the joints,
kidneys, and gut, and petechiae may be seen.
 Epiphyseal separation distal femur; upper tibia and humerus
 Scorbic rosaries due to costochondral separation
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64. IMAGING
 Pencil thin cortex – osteopenia is the first change seen, with thinning of the
cortices.
 White Line of Frankel - the zone of provisional calcification increases in width
and opacity because of failure of resorption of the calcified cartilaginous matrix,
and it stands out in comparison to the severely osteopenic metaphyses.
 Trummerfield’s zone of rarefaction
 Wimberger’s ring sign - the margins of the epiphyses appear relatively sclerotic,
a finding termed ringing of the epiphyses, or Wimberger sign.
 Pelkan’s Spur - lateral spur formation at the ends of the metaphysis is produced
by outward projection of the zone of provisional calcification.
 Corner sign of Park –or angle sign of scurvy is a peripheral metaphyseal cleft
caused by a defect in the spongiosa and cortex adjacent to the provisional zone
of calcification.
 Scurvy line or scorbutic zone - a radiolucent transverse band adjacent to the
dense provisional zone.
 Ground-glass appearance
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66. DDX
 osteomyelitis
 Polio
 Leukemia
 Purpuric conditions, such as Henoch-Schönlein purpura and
thrombocytopenic purpura
 Syphilis
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67. TREATMENT
 Vitamin C supplements & rich food
 Scurvy is prevented by adequate intake of vitamin C, defined as
25 mg/day for infants, 30 to 40 mg/day for children and 40
to 75 mg/day for adults. Intoxication does not occur.
 Immobilize #s and painful joints with plaster splints
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