CONNECTIVE TISSUE DISORDERS Anna Junkiert-Czarnecka 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.

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

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) 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)

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