1. CONNECTIVE TISSUE DISORDERS
Anna Junkiert-Czarnecka
Department of Clinical Genetics
Julian Voss-Andreae Unraveling Collagen, Orange Memorial Park Sculpture Garden, San Francisco, CA

2. 1. Ehlers-Danlos syndrome
2. Marfan syndrome
3. Osteogenesis Imperfcta

3. 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: :50 000

4. 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.

5. The inheritance pattern
Type of EDS
The inheritance pattern
classic, AD
hypermobility,
vascular,
kyphoscoliotic, AR
arthrochalasia,
dermatosparaxis,
Additional types represent autosomal dominant or recessive,
as well as X-linked type of inheritance

6. 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).

7. ≥4 = hypermobility of joints

8. 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 -.

10. 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

11. 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.

12. 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

13. Hypermobility Type Most common type (1 in 10-15,000)
Joint hyperextensibility
Chronic degenerative joint disease
Less skin involvement

14. Diagnosis Family History/Pedigree Physical Exam
Skin biopsy biochemical analysis for structure of collagen
Genetic testing

15. 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

17. 1. Ehlers-Danlos syndrome
2. Marfan syndrome
3. Osteogenesis Imperfcta

18. Marfan syndrome genetic disorder of the connective tissue
First described in 1896; named in 1902.
Common inherited connective tissue disorder
Incidence: 1 in ; approximately 200,000 Americans affected
It affects men, women, and children.
Found among people of all races and ethnic backgrounds

19. Genes Genes involved in Marfan Syndrome phenotype:
FBN-1 which encodes the connective protein fibrillin-1
TGFBR

20. Clinical manifestation - skeleton
long legs, arms and fingers
(arachnodactyly)
high, arched (Gothic) palate
hyperextensibility of joints
spinal deformities,
pigeon breast

21. Marfan syndrome

22. 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)
Untreated Marfan’s is a/w dissection: usually type 1 or type A. Often, there is family h/o dissection as well.
In patients under age of 40, approx 50% of those cases are related to Marfan’s dz (also in differential is cocaine)

24. Osteogenesis Imperfecta (O.I.)
(Brittle bone disease)

25. 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

26. 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

27. 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

28. 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.

29. 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

30. 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