Download CONNECTIVE TISSUE DISORDER

CONNECTIVE
TISSUE
DISORDERS
Anna JunkiertCzarnecka
Department of
Clinical Genetics
Julian Voss-Andreae Unraveling Collagen, 2005.
Orange Memorial Park Sculpture Garden, San
Francisco, CA
• 1. Ehlers-Danlos syndrome
• 2. Marfan syndrome
• 3. Osteogenesis Imperfcta
What is Ehlers-Danlos Syndrome
(EDS)?
• The Ehlers-Danlos syndrome (EDS) (MIM
#130000) is a non-inflammatory, heritable
connective tissue disorder, caused by a defect in
the structure, production, or processing of
collagen or proteins that interact with collagen
• The world-wide prevalence of EDS is estimated
at 1:20 000-1:50 000
Classification of EDS
• According to Villefranche classification of Ehlers-Danlos
syndrome proposed in 1997, EDS is divided into six
major types:
- classic,
- hypermobility,
- vascular,
- kyphoscoliotic,
- arthrochalasia,
- dermatosparaxis,
- and additional types like X-linked EDS, familial
hypermobility, periodontitis type, etc.
Type of EDS
The inheritance pattern
classic,
AD
hypermobility,
AD
vascular,
AD
kyphoscoliotic,
AR
arthrochalasia,
AD
dermatosparaxis,
AR
Additional types represent autosomal dominant or recessive,
as well as X-linked type of inheritance
The classic EDS (cEDS)
• The classic EDS type (cEDS) occur most
frequently
• cEDS is characterized by:
- hypermobility of joints (hypermobility may lead to
subluxation and dislocations of the ankle joints,
shoulder, patella, hip. Hip dislocation at birth is
frequently observed).
≥4 = hypermobility of joints
The classic EDS (cEDS)
- hyperextensibility of skin, and
widened atrophic scars,
- pain
- other prominent features of cEDS
include smooth, velvety skin, easy
bruising, muscle hypotonia and
delayed motor development
-.
The classic EDS (cEDS)
• As a result of tissue fragility widened atrophic scars,
hiatal hernia, also postoperative hernias, anal prolapse
in childhood, cervical insufficiency, vaginal tears also
been noted.
• Pregnant women with cEDS have an increased risk for
premature rupture of fetal membranes, tear of the
perineal skin, prolapse of the uterus and/or the
bladder after delivery
The molecular basis of cEDS
• The molecular basis of classic Ehlers-Danlos syndrome is
essentially a deficiency of type V collagen.
• The type V collagen is a heterodimer composed of two α1(V)
chains and a single α2(V) chain which are encoded by the
COL5A1 and COL5A2 respectively. Mutations in COL5A1 and
COL5A2 gene have been identified in patients with classic
type of Ehlers-Danlos syndrome as the mutations responsible
for the disease.
Vascular Type
• Most serious type
• Prone to ruptured arteries and
aneurysms, intestinal and uterine
rupture
• Easy bruising
• Visible veins beneath thin,
translucent skin
• Joint involvement variable
• Relative deficiency in type III
collagen, encoded by COL3A1
gene
Hypermobility Type
•
•
•
•
Most common type (1 in 10-15,000)
Joint hyperextensibility
Chronic degenerative joint disease
Less skin involvement
Diagnosis
• Family History/Pedigree
• Physical Exam
• Skin biopsy biochemical analysis for structure of
collagen
• Genetic testing
Socio-Emotional Concerns
• Most people with EDS look normal
• The condition isn’t always taken seriously by
doctors, family, and friends
• Can be isolating
• General lack of awareness and understanding
can lead to feelings of frustration, stress, and
depression
• 1. Ehlers-Danlos syndrome
• 2. Marfan syndrome
• 3. Osteogenesis Imperfcta
Marfan syndrome
•
•
•
•
genetic disorder of the connective tissue
First described in 1896; named in 1902.
Common inherited connective tissue disorder
Incidence: 1 in 3000-5000; approximately 200,000
Americans affected
• It affects men, women, and children.
• Found among people of all races and ethnic
backgrounds
Genes
• Genes involved in Marfan Syndrome phenotype:
– FBN-1 which encodes the connective protein
fibrillin-1
– TGFBR
Clinical manifestation - skeleton
• long legs, arms and fingers
(arachnodactyly)
• high, arched (Gothic) palate
• hyperextensibility of joints
• spinal deformities,
• pigeon breast
Marfan syndrome
Cardiovascular Complications
• Aortic root disease  aneurysms, dissection
• Mitral valve prolapse
• Arrhythmias
Eyes
In Marfan syndrome the
principal change in eyes is
partial lens dislocation
(the lens is shifted out of
its normal position)
Osteogenesis Imperfecta (O.I.)
(Brittle bone disease)
General Information
• Group of rare genetic defects that affects the body’s
production of type I of collagen
– Collagen is main protein in connective tissue
• General Characteristics:
– Fragile or brittle bones
– Weak muscles
General Information
• Autosomal dominant trait
• Baby has 50% chance of inheritance from either mother
or father
– Spontaneous mutation of the collagen gene
• Affects 1 in 20,000-60,000 births
• Affects males & females equally
OI - types
• Type I
– Most common & mildest form
– Bone fractures are common during childhood &
adolescence from minor trauma (fractures less frequent
during adulthood)
– Normal or near-normal stature
– Loose joints and muscle weakness
– Sclera (whites of the eyes) usually have a blue, purple, or
gray tint
– Bone deformity absent or minimal
– Hearing loss possible
– Normal life expectancy
OI Types & Characteristics
• Type II
– Most severe form
– Frequently lethal at or shortly after birth, often
due to respiratory problems.
– Numerous fractures and severe bone deformity.
– Small stature with underdeveloped lungs.
OI Types & Characteristics
• Type III (Progressive)
–
–
–
–
–
–
–
Bones fracture easily, sometimes even before birth
Bone deformity, often severe
Short stature
Loose joints
Poor muscle tone in arms and legs
Early loss of hearing
Life expectancy shorter than normal
OI Types & Characteristics
• Type IV
–
–
–
–
–
–
–
Between Type I and Type III in severity
Bones fracture easily, especially before puberty
Short stature, spinal curvature and barrel-shaped rib cage
Bone deformity is mild to moderate
Discoloration of the sclera (whites of the eyes)
Early loss of hearing
Normal life expectancy