BIODATA SINGKAT

NAMA : dr. MAKSUM PANDELIMA, Sp. OT

TTL : BANDUNG / 08 JULI 1971
PANGKAT/NRP : LETKOL CKM NRP. 11950008540771
JABATAN : KARUMKIT TK III BALADHIKA HUSADA
TELP/ HP : 08113634335
STATUS : K3

PENDIDIKAN
UMUM
1. FK UNAIR – PENDIDIKAN DOKTER TAHUN 1997
2. SPESIALIS ORTHOPAEDI DAN TRAUMATOLOGI TAHUN 2010
3. FELLOW FOR SHOULDER AND KNEE ARTHROSCOPY TAHUN 2011

MILITER
1. SEPA PK TAHUN 1995
2. SESARCAB KES TAHUN 2000
3. DIKLAPA II TAHUN 2012
 KELAINAN
KONGENITAL
MUSKULOSKELETAL
UMUM
Maksum Pandelima, MD
RST dr Soepraoen/ FK Univ Islam Negeri Malang
2018
Osteogenesis Imperfecta
WH
O?
Meaning:  imperfect  bone  formation

Also  Known  As:

• Brittle  Bone  Disease
• Brittle  Bone  Syndrome
Q: WHAT IS OSTEOGENESIS IMPERFECTA?
A:  OI  is  a  genetic  disorder  
SYMPTOMS:
the  affects  the  gene  that  
produces  collagen  in  your   q multiple,  frequent  fractures
body.  Collagen  is  a  
q muscle  weakness
protein  that  connects  
tissues  in  your  body.  It   q joint  laxity
also  helps  with  the  
q curved  bones
formation  of  teeth,  
ligaments,  and  sclera   q Scoliosis
(white  outer  tissue  of  the  
q brittle  teeth
eyeball).
By  looking  at  a  person,  you  MAY  be   q short  stature
able  to  tell  if  they  had  OI  by  their   q blue  sclera
abnormally  small  stature,  the  whites  of  
their  eyes  being  a  blue  color,  they   q fragile  skin
would  have  a  triangular  head  shape,   q triangular  head  and  face  shape
and  could  potentially  be  using  a  
walker,  wheelchair,  or  have  casts  on  at   q respiratory  complications
the  time.  However,  some  people  with  
OI  have  relatively  mild  symptoms  and  
you  MAY  NOT  notice  that  they  look  
different  in  any  way.
How Common is it?

A  range  of  25,000  to  

50,000  Americans  
are  affected  by  OI.  
This  wide  range  is  
Worldwide,  about  1  
due  to  the  fact  that  
in  every  20,000  
very  mild  cases  of  
people  have  OI.  
OI  often  go  
Generally,  it  is  a  
unnoticed  and  are  
rare  disease.
not  diagnosed.  
 Definition

— Genetic disorder characterized by bone that break

easily often from little or no causes
àOne of the commonest genetic disorder of the bone
àIncidence 1 in 20 000
 Pathology

— Defect in chromosome no 17
Reduction in total amount of type I
collagen
Inheritance Patterns and Gene Location

35%  of  OI  cases  are  a  

result  of  spontaneous  
mutations,  while  the  
others  come  from  
Dominant  or  Recessive? parents  affected  by  OI  
About  85%-­90%  of  OI   or  parents  who  are  
cases  that  are  inherited   carriers.  
are  inherited  in  dominant  
manner.  There  are  some  
rare  instances  where  the  
disorder  is  recessive  an   The  mutations  that  
autosomal  however.  The   cause  collagen  
different  inheritance   problems  can  affect  
patterns  may  also  deal   either  the  quantity of  
with  slightly  different   collagen  or  the  
genes. quality of  the  
collagen  produced.
Inheritance Patterns and Gene Location
Continued…

The  gene  for  Osteogenesis  

Imperfecta  is  located  on  
chromosome  17  which  has  81  
million  base  pairs.

Chromosome  17
— Alteration in structural integrity of collagen type I

Type I collagen is a major component of the

connective tissues in bones, ligaments, teeth, and
the white outer tissue of the eyeballs (sclera).

— àThe result in both cases is the same: fragile

bones that break easily. However, the bones heal at
a normal rate
 Clinical feature
— Fracture after minor trauma
Classic type discover during infancy
mild case develops when start to walk
recur frequently
new bone formation is abnormal
Fracture because of coughing
— Age of 6 year
àDeformity of long bone
àVertebra compression fracture
— Skin is thin
— Joint hyper mobile
— Blue or grey sclera due to uveal pigment showing
through hyper translucent cornea.
— Discolored and caries teeth
 X- ray

— Thinning of the long bone

— Fracture in various stage of healing
— Vertebral compression
— Spinal deformity
 Differential diagnostic

— Type III must be differenciated from infantile

hypophospatemia
àsevere osteoporosis + mikromelia
àlow alkaline phosphatase
— Type I
— Most common and mildest type of OI.
— 50 % of the causes
— Bones predisposed to fracture. Most fractures occur
before puberty.
— Normal or near-normal stature.
— Loose joints and low muscle tone.
— Sclera (whites of the eyes) usually have a blue,
purple, or gray tint.
— Tendency toward spinal curvature.
— Bone deformity absent or minimal.
— Hearing loss possible, often beginning in early 20s or
30s.
— Collagen structure is normal, but the amount is less
than normal.
— Autosomal dominan inheritance.
— Type II
— Most severe form.
— Frequently lethal at or shortly after birth, often due
to respiratory problems. In recent years, some people
with Type II have lived into young adulthood.
— Numerous fractures and severe bone deformity.
— Small stature with underdeveloped lungs.
— Collagen is improperly formed.
— Large skull
— Grey sclera
— Most due to new dominant mutation, some
autosomal recessive
— Type III
— Bones fracture easily. Fractures often present at
birth, and x-rays may reveal healed fractures that
occurred before birth.
— Sclera have a blue, purple, or gray tint.
— Loose joints and poor muscle development in arms
and legs.
— Barrel-shaped rib cage.
— Spinal curvature.
— Respiratory problems possible.
— Bone deformity, often severe.
— Dentinogenesis imferpecta
— Hearing loss possible.
— Collagen is improperly formed.
— Autosominal recessive
— Type IV

— Bones fracture easily, most before puberty.

— Shorter than average stature.
— Sclera are white or near-white (i.e., normal in color).
— Mild to moderate bone deformity.
— Tendency toward spinal curvature.
— Brittle teeth possible.
— Collagen is improperly formed.
— Survive to adulthood
— Autosomal dominan inheritance
 Management

Treatment goals include:

— Maximizing function
— Minimizing disability
— Fostering independence and social skills
— Maintaining overall health
— Most treatment even in fracture –Conservativelly
— Bracing, splinting
— Immobilize not to long à worsen the osteopenia
— Operative indication
Repeat fracture in the same bone
Deformity
Improper fracture healing
 How does OI affect a
person’s life?
Based on the type of OI, a
person’s lifespan could be affected
very little, while it can also be
drastically affected. There are 8
different types of OI. Similar
symptoms may occur in all types
of OI with varying severity.
Different symptoms may also show
up within the same type.
How does OI affect a person’s life?

TYPE  I:  mildest  and  most  common  form  of  disorder;;  does  
not  usually  affect  lifespan  unless  a  severely  traumatic  event  
occurs;;  most  fractures  occur  during  youth  and  adolescence
TYPES  II  and  III:  most  severe  types;;  infants  with  TYPE  II  
commonly  die  during  pregnancy  or  shortly  after  birth  ,  
however  some  with  TYPE  III  may  survive  longer  but  with  
many  disabilities  and  traumatic  events
TYPES  IV-­VII:  moderate  forms  of  disease;;  lifespan  not  
dramatically  affected;;  more  rare  than  type  I  and  deal  with  
different  genes
TYPE  VIII:  more  severe  type  similar  to  types  II  or  III  but  
some  symptoms  vary
*There  is  no  certain  reduced  life  expectancy,  but  with  more  
severe  cases  of  OI  the  probability  of  death  from  accidental  
trauma  or  respiratory  complications  is  highly  increased.
-­Respiratory  problems  and  accidental  trauma  are  
the  most  common  deaths  of  people  who  have  OI.
Can a person be tested How is OI treated?
for OI?
YES.  Testing  can  take  place  to  
make  a  diagnosis  if  a  person  
There  is  no  cure  for  OI  as  of  right  
is  showing  symptoms  of  OI.  
now.  However,  there  are  some  
Tests  can  also  be  planned  for  
ways  of  dealing  with  the  disorder.  
children  whose  families  have  
Biophosphonates  and  other  
been  affected  by  OI.  Testing  
medicines  are  used  to  make  bones  
and  diagnosis  is  usually  done  
stronger  and  more  dense,  and  
during  childhood,  and  a  
surgically  placing  rods  in  the  
diagnosis  can  sometimes  be  
bones  of  the  legs  often  help  
made  during  pregnancy.  
prevent  major  fractures.  There  are  
Methods  of  testing  include: minor  symptoms  of  the  
biophosphonates,  including  
o X-­Rays
stomach  upset  and  heartburn.  On  
o DNA  sequencing  using  a  collagen   a  regular  basis,  doctors  and  
sample  from  blood families  focus  on  mobility  and  
safe  exercise  such  as  swimming  
o Biochemical  tests  using  a  
and  physical  therapy,  as  well  as  
collagen  sample  from  the  skin
keeping  fracture  numbers  to  a  
o tests  during  pregnancy  can  be   minimum.    Braces,  wheelchairs,  
done  through  ultrasound  and   and  casts  are  useful  aids  as  well.
amniocentesis  
 INTERESTING FACTS

*Parents  of  children   *OI  was  

with  OI  are  often   recognized  in  an  
accused  of  child   Egyptian  mummy  
abuse,  which  is  why   that  is  dated  
they  are  advised   back  to  1000  BC.
always  to  carry  a   • OI  does  not  affect      
document  stating   fertility.
their  child’s   *The  2  forms  of  OI  
condition  so  that   that  are  inherited  
their  kids  aren’t   recessively  were  
taken  from  them  at   discovered  only  4  
any  point. year  ago.
Fibrous Dysplasia
 Definition

— Benign condition in which normal bone is replaced

by fibrous connective tissue due to a defect in
osteoblast differentiation and maturation
 Epidemiology

— Incidence not known

— Females > males
— No race predilection
— Initial symptoms manifest age 3-15
— Not heritable
— Questionable genetic transformation
— Malignant transformation in < 1%
 Variations

— Cystic (21%)
- Radiolucency surrounded by solid rim

— Sclerotic (23%)
- Dense and homogenous

— Mixed (56%)
- “Ground glass appearance”
 Variations, cont’d

— Monostotic
- Most common
- 25% involve head and neck
— Polyostotic
- 15% of cases
- 50% involve head and neck
Where you at?
 Images
— Left temporal bone
involvement
 Images
— Right temporal bone
lesion
Images
 Presentation

— Local pain
— Swelling
— Abnormal pigmentation
— CN compression
— Spontaneous scalp hemorrhage
— Part of McCune-Albright’s syndrome
 McCune-Albright’s Syndrome

— Polyostotic fibrous dysplasia

— Café-au-lait spots
— Endocrinopathology:
- Hyperthyroidism
- Precocious puberty in females
 Imaging

— Plain radiography is first line

— Computed tomography for complex regions
 Histology
— Fibroblasts within
woven cancellous
bone
 Differential Diagnosis

— Eosinophilic granuloma
— Nonossifying fibroma
— Bone hemangioma
— Hyperparathyroidism
— Paget’s disease
— Brown’s tumor
— Aneurysmal bone cyst
 Treatment

— No available cure
— Curettage
— Cranioplasty
— Calcitonin
 The One Slide To Remember

— Genetic, non-heritable disorder

— <1% transformation to malignancy
— Treatment is curretage or cranioplasty
 References

— Greenberg, M. Handbook of Neurosurgery 6th

Edition. Thieme: New York 2006
— Kaye AH, Black P McL. Operative Neurosurgery Vol
2. Harcourt Publishing: New York 2000
— Dal Cin P, Sciot R, Spelenberg F, et al. Chromosome
Aberration in Fibrous Dysplasia. Cancer Genet
Cytegent 1994 Oct15;77(2) 114-7
 Marfan Syndrome
and related disorders
 Overview

— Epidemiology
— Genetics/Pathophysiology
— Diagnosis/Clinical Features
— Management
— Differential Diagnosis
 Epidemiology

— First described in 1896; named in 1902.

— Common inherited connective tissue disorder
— Incidence: 1 in 3000-5000; approximately 200,000
Americans affected
— M = F; men with shorter life expectancy
— Races affected equally
 Genetics

— Autosomal dominant; variable expression

— ~25% spontaneous mutations
— Genes involved in Marfan Syndrome phenotype:
¡ Fibrillin-1 (MFS)

÷ Microfibril glycoprotein in both elastic and non elastic tissues

÷ > 97 different mutations
¡ TGFBR (MFS type II or Loeys-Dietz)

÷ Works through apoptosis and cell cycle regulation; prevents

proper incorporation of fibrillin into tissue
÷ Also with triad: hypertelorism, bifid uvula or cleft palate,
generalized arterial tortuosity
— Other gene mutations may lead to similar phenotypes
Abraham Lincoln
 Diagnosis

— Clinical diagnosis: the Ghent criteria

¡ physical exam: 6 organ systems involved
¡ family history
¡ genetic testing

— If (+) family history, additionally you need:

¡ Involvement of 2 organ systems including 1 major criterion

— If (–) family history, additionally you need:

¡ Major criterion from 2 systems and involvement of a 3rd
system
 Clinical Features

— HEENT:
¡ Eye: superior lens dislocation (ectopia
lentis)
¡ Oropharynx: high palate and crowded
dentition
— Cardiac:
¡ Mitral valve prolapse

¡ Aortic root dilation

— Pulmonary: Spontaneous pneumothorax

— Neurologic: Dural ectasia
— Skin: Stretch marks
 Clinical Features

— Musculoskeletal:
¡ Tall stature (dolichostenomelia)
¡ Long digits (arachnodactyly)
¡ Thumb sign (distal phalanx protrudes
beyond border of clenched fist)
¡ Wrist sign (thumb and fifth digit overlap
when around the wrist)
¡ Sternal deformity (prominent pectus)
¡ Scoliosis > 20 degrees
¡ Joint hypermobility
¡ Arm span exceeding height (ratio >1.05)
¡ Reduced elbow extension (<170 degrees)
¡ Medial displacement of medial malleolus
Jonathan Larson, playwright/composer
 Cardiovascular Complications

— Most common cause of M&M (~80%)

— Aortic root disease à aneurysms, AR, dissection
¡ In 50% children
¡ In up to 80% of adults
¡ May lead to neurovascular complications
¡ AR murmur: decrescendo, diastolic

— Mitral valve prolapse (minor criterion)

¡ In 60-80% patients; most common valve disorder
¡ Worsens with time, complicated by rupture
¡ MVP murmur: ejection click, holosystolic

— Arrhythmias
 MKSAP Question

A 22-year-old man is evaluated as part of a routine

examination...He is 171.5 cm (78 in) tall and weighs 72.8 kg (185 lb)
with pectus excavatum. Blood pressure is 134/65 mm Hg bilaterally,
and pulse rate is 76/min and regular. He has a high arched palate.
There is a 2/6 decrescendo diastolic murmur at the right upper
sternal border while in the upright posture. There is moderate
scoliosis, joint hypermobility, and the patient's thumb and fifth digit
overlap when circling the opposite wrist (“wrist sign”).

What’s the most appropriate next step in management?

A Chest radiograph
B Transthoracic echocardiogram
C Aortic magnetic resonance angiogram
D Transesophageal echocardiogram
 Management: screening/counseling

— Annual echocardiogram
— Annual ophtho exam and
orthopedic involvement
as needed
— Counseling regarding
physical activities
— Genetic counseling
 Management: medications

— Beta blockade
¡ Standard of care for adult patients (no data on children)
¡ Based on studies of propranolol versus placebo
÷ Slower rate of aortic dilatation with beta blockade
÷ Survival at 10 yrs not significantly improved

— Calcium channel blockers?

— ARBs
¡ Recent animal study models of FBN1 mutants demonstrated
decreased rate of aortic dilatation
¡ Mechanism is via TGFBR
¡ One randomized trial of 17 patients is complete: larger study is
now ongoing
 Management: surgical intervention

• Better survival with elective repair

• Variable recommendations for aortic root diameter
at which intervention warranted
– ACC/AHA: diameter > 5.0 cm
– ESC: diameter > 4.5 cm
– Rate of increase > 0.5 cm/year
• Earlier intervention indicated in women desiring
pregnancy
• Annual imaging post-op still necessary
 Similar phenotypes

— Congenital contractual arachnodactyly: FBN2

— MASS (Mitral valve prolapse, aortic dilation, skin
and skeletal abnormalities): FBN1
— Joint hypermobility syndrome
— Ehlers-Danlos: mutation of type V collagen
— Stickler syndrome: mutation of type II and XI
collagen
 Take home points

— Marfan Syndrome is relatively common

— If you have a patient < 40 with evidence of aortic
root changes, think MFS
— No cure, so cardiovascular management is key
¡ Annual echo
¡ Beta blockade
¡ Counseling on physical activity
 References

— Lacina, S. What’s new in outpatient cardiology. Curr Opin

in Ped. 2009; 21:605-610.
— Midla, G. Diagnosis and management of patients with
Marfan syndrome. JAAPA 2008; 21(2): 21-25.
— Attias, D, et al. Comparison of Clinical Presentations and
Outcomes Between Patients with TGFBR2 and FBN1
Mutations in Marfan Syndrome and Related Disorders.
Circulation 2009; 120: 2541-2549.
— Loeys, B, et al. Aneurysm Syndromes Caused by Mutations
in the TGF-B Receptor. NEJM 2006;355:788-798.
Myotonia Congenital
 Disclosure Statement

— NIH: 8U54 NS059065 funding for the Consortium

for Clinical Investigation of Neurological
Channelopathies

— Port Elgin Rotarians for patient-centered Muscular

Dystrophy Research
 Nondystrophic Myotonias
disorders of muscle membrane excitability
painless muscle stiffness

— chloride channelopathies (CLCN1)

¡ myotonia congenita (MC)
÷ autosomal dominant (Thomsen) 1876
÷ autosomal recessive (Becker) 1977
¡ myotonic dystrophy type 1 and 2

— sodium channelopathies (SCN4A)

¡ paramyotonia congenita (PMC)
¡ potassium-aggravated myotonia (PAM)
÷ AZM-responsive myotonia
÷ myotonia fluctuans and myotonia permanens
¡ hyperkalemic periodic paralysis (HyperPP)
 Caveats

— marked phenotypic variability within and

between affected individuals and kindreds (e.g.
Thomsen pedigree P480L )
¡ dominant mutations with reduced penetrance
¡ asymptomatic heterozygotes in AD pedigrees
¡ identical mutations in dominant and recessive
pedigrees
¡ kindreds with unusual features
— modifying genes and/or environmental factors
yet to be determined
— need for prospectively collected, standardized
data
— 27 yo male with muscle stiffness
— went to his family physician at age 12
¡ parents and teachers were “hassling” him to “try harder”
¡ “last kid off the mark in gym class”

— knew he “couldn’t keep up” in ? grade 1 but “tried to

hide it by constantly moving”
— responds well to mexiletine
— 2 sisters also affected, but to a lesser degree
— parents clinically and (dad electrophysiologically)
unaffected
— ocular myotonia; lid lag; percussion and grip
myotonia - improves with repetition
— hypertrophy of thoracolumbar paraspinals, thigh
and leg; mild restriction of ankle dorsiflexion
— 37 yo male with lifelong muscle stiffness (father
similarly affected)
— onset in infancy: stiffness noted with rolling over
and crawling; frequent falls when learning to walk
— stiffness is painless and improves with activity
¡ stopped playing hockey as a teenager – fell on the ice,
unable to “jump over the boards”
¡ continues to golf and play tennis – uses continual motion
to stay loose
— “worse in the cold”
— flecainide 100 mg bid helpful (tocainide was better)
— delayed eye opening with forced eye closure, better
with repetition; lid lag; mild percussion, grip (and
widespread electrical) myotonia
— well-developed musculature
 MC: AR and AD

— typically onset in 1st decade

— painless muscle stiffness; mild to severe
— “warm-up”
may not be prominent if severe myotonia
— triggers incl activation after rest, stress/startle,
pregnancy
Exam……….
— muscle hypertrophy (+/- atrophy)
— ocular, grip and percussion myotonia w/ warmup
— lid lag
— stair test
¡ 10 stairs ~ 4 seconds if unaffected
EDX – diffuse electrical myotonia
 AR (vs. AD)

— absent family history

— older onset
— more severely affected ; 15-20% painful
— leg onset (vs. face/hands in AD)
— males ± more severely affected than females
— transient weakness
— ± progressive into 4th decade
— ± focal atrophy (distal forearms and neck)
— a proportion develop fixed weakness
 Lumpers vs. Splitters

Cl  vs  Na MC+v,  PAM+v,  PMC

Big  picture  gal? Detail  guy?

 Myotonia Congenita Variants

— due to CLCN1; dominant inheritance

¡ myotonia levior
÷ milder, later onset, grip stiffness after rest
÷ no hypertrophy

¡ fluctuating myotonia congenita (G200R)

÷ painful; legs > arms
÷ percussion and grip myotonia
÷ fluctuates with symptom free intervals
÷ stiffness with activation after rest, pregnancy, fasting, stress
 and…Potassium Aggravated
Myotonia (PAM)

— sodium channelopathies (SCN4A); often AD

¡ potassium and exercise trigger symptoms
¡ do not worsen after cold exposure
¡ do not have episodic weakness
÷ myotonia fluctuans
¢ asymptomatic periods; worsening myotonia with delay after start
of exercise; ocular paramyotonia
÷ acetazolamide responsive myotonia
¢ painful; may worsen throughout childhood and adolescence with
dramatic improvement with ACZ
÷ myotonia permanens (G1306E) sporadic
¢ severe, persistent myotonia of face, limbs and intercostals;
hypertrophy of neck and shoulder muscles; ± respiratory
compromise
inheritance Thomsen  AD Becker  AR PAM  AD PMC  AD
clinical   mild-­moderate mod-­severe fluctuating  to   mild-­mod
myotonia face;;  UE  >  LE LE  >  UE severe face,  UE,  LE
age  of  onset 1st decade 1st -­2nd decade late  1st decade late  1st decade
childhood

triggers rest rest exercise,  K exercise,  cold

warm-­up improves improves ? worsens

cold no  effect no  effect not  really myotonia  worse;;  

± paralysis
episodic   no ± transient   no yes
weakness proximal
lid  lag yes yes yes yes

hypertrophy mild mod ARM  and  MP ±

treatment mexiletine mexiletine mexiletine mexiletine

flecanide flecanide acetazolamide acetazolamide

gene CLCN1 CLCN1 SCN4A SCN4A

 Questions to be answered

— Will the differences in clinical phenotype combined

with EDX studies accurately predict genotype?
— What additional genetic and/or environmental
factors are responsible for the intra- and inter-
familial phenotypic variability?
— Will treatment prevent the permanent weakness
seen in a proportion of NDM patients? How do we
identify those that will benefit from treatment?
 AR myotonia congenita
(Becker)

— ~ 1/50,000
— onset late in 1st decade; more severe than AD
— legs > arms; 15% painful
— warm-up helpful for most, but not all
— triggered after rest, stress, worsens during pregnancy
— grip, neck > tongue myotonia; lid lag ~50%
— hypertrophy often of gluteal and leg muscles with atrophy
of forearm muscles
— transient weakness but % will develop permanent
weakness
— ± wrist and ankle contractures; toe walking
— CK normal to 2-3x ↑
 AD myotonia congenita
(Thomsen)

— ~1/15,000-25,000
— onset in infancy or early childhood
— face, tongue, pharyngeal muscles, hands and legs
— triggered by activation after rest, startle, stress,
increased in pregnancy
— “warm-up” will minimize stiffness
— muscle hypertrophy without weakness
— grip and percussion myotonia; lid lag and ocular
myotonia
— CK normal or mildly increased
 Electrophysiology Helps

— routine NCS (± after  potentials)

— EMG: myotonic potentials
— short exercise protocol with repetition ± cold
exposure

Fournier  et  al,  2006

more  in  the  afternoon  Neurophysiology  session!!

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