• Information
  1. Characteristics
  2. Types
  3. Diagnosis
  4. Loeys-Dietz Syndrome

A. Characteristics

1. Generalized connective tissue disorders
2. Hypermobile joints and anomalies of skin
3. Increased risk of osteoarthritis
4. Variable inheritance
5. At least 9 distinct types
   1. Usually grouped by mode of inheritance and manifestations
   2. AD = autosomal dominant, AR = autosomal recessive, XL = X linked
   3. Molecular defects have been discovered for many of the distinct types
   4. Abnormalities in collagen synthesis and/or processing underlie most EDS types
6. Overall EDS affects ~1 in 5000 persons

B. Types

1. Type I
   1. Autosomal dominant (AD)
   2. Hypermobile joints
   3. Marked skin fragility ("cigarette paper" thin skin)
2. Type II
   1. Type IIA - AD, milder form of type I, easily bruise but skin not fragile
   2. Type IIB - AR, rare form similar to IIA, aortic dilatation is not uncommon
3. Type III
   1. AD
   2. Marked joint hypermobility
   3. Mild skin involvement
4. Type IV (Vascular Form) [2,5]
   1. Only form of EDS associated with increased risk of death
   2. Aneurysm formation and rupture of arteries (can be fatal)
   3. Intestinal problems, usually sigmoid colon, including fatal rupture have been reported
   4. Marked skin fragility
   5. Complications of pregnancy
   6. Few or no joint problems
   7. Inherited AD, and recently Col3A1 Gene Deletion identified in affected persons
   8. Various mutations in collage Type III (Col 3A1) gene can cause EDS Type IV
   9. Some patients with Type IV have mutations in TGFß receptor I or II and likely have the Loeys-Dietz Syndrome [3,4]
   10. Patients with suspected ED Type IV should be screened first for Col 3A1 mutations
   11. If no Col 3A1 mutations found, then screen for TGFß receptor I or II mutations [3]
5. Type V - X-Linked similar to type II
6. Type VI
   1. Ocular fragility, keratoconus
   2. Hypermobile joints
   3. Soft, velvity hyperextensible skin
   4. Inherited as AR with abnormalities in lysyl hydroxylase
7. Type VII
   1. Three subtypes: A,B,C - AD or AR
   2. Types A and B have defects in COL1A2 with abnormal protease processing site
   3. Type C due to N-proteinase deficiency (inherited AR)
   4. Marked joint hypermobility, dislocations common
8. Type VIII
   1. AD
   2. Periodontitis
   3. Atrophic pigmented skin scars
   4. Marked joint hypermobility
9. Type IX
   1. Abnormal bone (short arms), mild joint and skin disease, bladder diverticuli, hernias
   2. Copper utilization defect
10. Type X
    1. AR inheritance with fibronectin defect
    2. Symptoms similar to Type II

C. Diagnosis

1. Mainly by clinical features initially
2. Culture of fibroblasts and molecular evaluation may be useful (not done routinely)
3. PCR gene analysis may be possible in near future
4. Surgical repair of aneurysms recomended, but high risk of intraoperative morbidity/mortality
5. No specific treatments

D. Loeys-Dietz Syndrome [3,4]

1. Mutations in TGFß receptor I (~30%) or II (~70%)
2. TGFß (transforming growth factor ß) is a major connective tissue stimulator
3. Syndrome Type 1
   1. Hypertelorism, cleft palate or bifid uvula, arterial tortuosity with aneurysms
   2. Other cardiovascular, skeletal, cutaneous findings
   3. Some central nervous system abnormalities
   4. No ectopic lens (which is common in Marfan Syndrome)
4. Syndrome Type 2
   1. Similar to Ehlers-Danlos Syndrome Type IV but without Col 3A1 mutations (see above)
   2. Prominent joint laxity, easy bruising, wide and atrophic scars
   3. Velvety and translucent skin, easily visible veins
   4. Sponaneous rupture of spleen or bowel
   5. Diffuse arterial aneurysms and sisections
   6. Catastrophic complications of pregnancy
   7. No cleft palate, hepertelorism, or cariosynostosis
5. Median survival 37 years

References

1. Pyeritz RE. 2000. NEJM. 342(10):730 (Editorial Review)
2. Pepin M, Schwarze U, Superti-Furga A, Byers PH. 2000. NEJM. 342(10):673
3. Gelb BD. 2006. NEJM. 355(8):841
4. Loeys BL, Schwarze U, Holm T, et al. 2006. NEJM. 355(8):788
5. Sareli AE, Janssen WJ, Sterman D, et al. 2008. NEJM. 358(6):626 (Case Record)