Connective tissue disorder

connective tissue disorder

1. Connective Tissue Disorder Dr. Deepesh Sharma(PT) MPT(Cardio-Pulmonary) Assistant Professor JNU College Of Physiotherapy , Jaipur

2. Introduction Connective tissue is an important biological tissue composed of an  extracellular matrix that binds, anchors, and supports organs . Over 200 conditions, which may be inherited or autoimmune, affect connective tissue and they are collectively known as connective tissue diseases (CTDs). Inherited CTDs are caused by mutations that affect one of the two fibers (collagen and fibrin). Autoimmune CTDs have no clear etiology, but the  incidence is higher in women and among genetically predisposed individuals. As the name suggests, in autoimmune CTDs, the immune system develops antibodies against components of connective tissue. Individual conditions can affect a vast range of bodily structures (including cartilage, blood vessels, bone, tendons, and organs) and thus present with a wide array of clinical findings.

3. Types Autoimmune connective tissue diseases Inherited connective tissue diseases

4. Autoimmune connective tissue diseases Systemic lupus erythematosus Rheumatoid arthritis Inflammatory myopathies  (e.g.,  polymyositis ,  dermatomyositis ) Systemic sclerosis Sjögren's syndrome Mixed connective tissue disease (Sharp's syndrome)

5. Inherited connective tissue diseases Ehlers- Danlos  syndrome Marfan syndrome Osteogenesis imperfecta Alport syndrome Loeys -Dietz syndrome  [1] Autosomal dominant inheritance Features shared with  Marfan syndrome:  marfanoid habitus , increased risk of ascending aortic aneurysms and aortic dissection Distinct features:  hypertelorism , bifid uvula, cleft palate, easy bruising and  keloids , arterial  tortuosity  (winding course of arteries)

6. Clinical manifestations of connective tissue disorders Clinical features vary greatly among individual diseases. The table below provides a general overview of the more common features.

7. Marfan syndrome (MFS) It is an  autosomal dominant connective tissue disorder affecting the microfibrils and  elastin  in connective tissue throughout the body.  MFS  is associated with pathological manifestations in the cardiovascular system (e.g., mitral valve prolapse , aortic aneurysm, and dissection), the musculoskeletal system (e.g., tall stature with disproportionately long extremities, joint  hypermobility ), and the eyes (e.g.,  subluxation of the lens of the eye).

8. Etiology & Pathophysiology Autosomal dominant disease caused by mutation of fibrillin-1 gene (FBN1) on chromosome  15 Defective  fibrillin  → defective  elastin  → defective connective tissue throughout the body

9. Clinical features Cardiovascular Features Aortic  necrosis  ( cystic medial degeneration ), characterized by histopathologic findings such as: Loss, thinning, disorganization, and fragmentation of  elastic fibers Accumulation of mucoid   extracellular matrix Loss of  smooth muscle  nuclei Aortic regurgitation Aor tic   aneurysm Thoracic or  abdominal aortic aneurysm Aortic root dilation :  aneurysm  of the  proximal   thoracic aorta Aortic dissection  Features of  mitral valve prolapse Berry aneurysms , which can rupture →  subarachnoid hemorrhage

10. Clinical features Musculoskeletal features Tall stature with rapid linear growth and long extremities Joint   hypermobility High-arched palate Arachnodactyly ( achromachia ): abnormally long, slender fingers and toes Pectus deformity:  pectus carinatum  ( sternal kyphosis ; more specific for  Marfan syndrome ) or  pectus excavatum Pes planus  (flat foot) or hindfoot valgus Spinal deformities ( scoliosis ,  hyperkyphosis )

11. Clinical features Skin Loss of skin elasticity/ striae  ( stretch marks ) Eyes Visual impairment:  ectopia lentis  ( lens dislocation )  →  lens subluxation   superiorly and temporally   Severe  myopia

12. Ehlers- Danlos  syndrome (EDS) It is a heterogeneous group of six connective tissue disorders with variable inheritance in which the synthesis and processing of collagen are defective. Patients present with varying degrees of hyperelastic skin, joint  hypermobility , and tissue fragility (including that of vasculature).

13. Etiology & Pathophysiology Etiology Heterogeneous group of six connective tissue disorders with variable inheritance ( autosomal recessive or dominant) Mutation in genes controlling synthesis of  collagen Classic type: mutations in COL5A1, COL5A2 → type V collagen  defect Vascular type: type III  procollagen   defect Pathophysiology Defective collagen cross-linking and fibril synthesis

14. Clinical Features Cardiovascular Features heart valve  defects (particularly  mitral valve prolapse ) Features of  aneurysms /dissections of the iliac, splenic , renal arterties , or the aorta Berry/ saccular aneurysms  of the cerebral  arteries  → features of  subarachnoid hemorrhage Musculoskeletal Joint   hypermobility  with tendency to dislocate  Skeletal abnormalitis (e.g.,  scoliosis ) Skin Tendency to  bruise  easily Skin hyperextensibility Frequent skin lacerations and poor skin healing (e.g., following surgery)  Other Hernias Features of organ rupture (e.g.,  shock , local  pain ), especially in vascular EDS

15. Prognosis Marfan syndrome: patients can expect a normal lifespan, if the disorder is diagnosed early and complications are managed appropriately  Aortic root disease is the most common cause of mortality Ehlers- Danlos  syndrome: Life expectancy is typically normal with the exception of vascular EDS, which has a reduced life expectancy of ∼ 50 years.

16. Osteogenesis imperfecta  (brittle bone disease) A genetic disorder characterized by defective synthesis of type 1 collagen, which is important in bone formation . Patients present with signs that are sometimes mistaken for child abuse (e.g., easy bruising, predisposition to bony fractures).

17. Etiology & Pathophysiology Etiology :   Autosomal dominant  mutation in  COL1A1  or  COL1A2  genes Pathophysiology : ↓ formation of hydrogen and disulfide bonds between type I  preprocollagen  molecules → ↓ triple helix formation → ↓ type I collagen synthesis → impaired bone matrix formation ( osteogenesis )  

18. Clinical features   Osteogenesis imperfecta  type I (the mildest and the most common form) Growth delay Skeletal deformities, brittle bones Bowing of bones and saber shins  Fractures during childbirth  and recurrently from minimal trauma thereafter Blue sclerae   Progressive hearing loss  Brittle, opalescent teeth ( dentinogenesis imperfecta ; due to a lack of dentin) Ligamentous laxity and joint  hypermobility Osteogenesis imperfecta  type II Most severe form; lethal prenatally or within the first year Multiple intrauterine and/or preinatal  fractures Underdeveloped lungs and subsequent respiratory problems

19. Scurvy Clinical manifestation of vitamin C deficiency, which leads to impaired collagen synthesis and easily damaged connective tissue.

20. Clinical features Swollen gums Mucosal bleeding Poor wound healing Curly body hair Follicular hyperkeratosis Hemarthrosis Generalized weakness/fatigue

21. Systemic lupus erythematosus (SLE) It is a multisystem autoimmune disease that predominantly affects women of childbearing age. The exact cause is still unknown, but hormonal and immunological influences as well as genetic predisposition are considered likely etiological factors. The presentation of the disease is variable and may range from mild localized symptoms to life-threatening systemic disease.

22. Epidemiology Sex : ♀ >> ♂ (10:1) Peak incidence: women aged 20–40 years; no particular age of manifestation in men

23. Etiology The exact etiology is unknown, but several predisposing factors have been identified: Genetic predisposition: HLA-DR2 and HLA-DR3 are commonly present in individuals with SLE Genetic deficiency of classical pathway complement proteins (C1q, C2, C4)  Hormonal factors: studies suggest that  hyperestrogenic  states (e.g., due to oral contraceptive use, postmenopausal hormonal therapy, endometriosis) are associated with an increased risk of SLE.  Environmental factors: UV light, stimulation of immune cells through infection with bacteria and viruses,   medications.

24. Pathophysiology Possible mechanisms for the development of  autoantibodies Deficiency of classical complement proteins (C1q, C4, C2) → failure of macrophages to  phagocytose   immune complexes and apoptotic cell material (i.e., plasma and nuclear antigens)  → dysregulated , intolerant lymphocytes begin targeting normally protected intracellular antigens → autoantibody production (e.g.,  anti- ds  DNA) Mechanism of tissue damage Type III hypersensitivity→  antibody-antigen complex formation in microvasculature → complement activation and inflammation → damage to skin, kidneys, joints, small vessels Type II hypersensitivity →  IgG  and  IgM antibodies directed against antigens on cells (e.g., red blood cells) →  cytopenia

25. Clinical features Skin (> 70% of cases) Malar rash (butterfly rash) with sparing of the  nasolabial folds Photosensitivity Discoid rash  Oral ulcers Alopecia ( nonscarring ) Joints Arthritis and  arthralgia  (> 90% of cases) Mostly  nonerosive   polyarthritis  (normal x-ray) Fever (> 50% of cases), fatigue (> 80% of cases), weight loss

26. Other signs and symptoms Musculoskeletal :  myalgia  and  lymphadenopathy Serositis :  pleuritis  and  pericarditis ; effusions and chest pain may occur Kidneys : nephritis with  proteinuria   Heart : involvement of the myocardium, pericardium, valves, and coronary arteries Lungs :  pneumonitis , interstitial lung disease, pulmonary hypertension Gastrointestinal :  esophagitis , hepatitis, pancreatitis  Vascular :  Raynaud phenomenon ,  vasculitis ,  thromboembolism   Neurologic : e.g., seizures, psychosis, personality changes, aseptic meningitis,  polyneuropathy , myasthenia gravis Hematologic : hemolytic anemia, thrombocytopenia,  leukopenia Eyes :  keratoconjunctivitis sicca

27. Sjogren syndrome Sjogren syndrome is a chronic inflammatory autoimmune disease that occurs mainly in middle-aged women. The cause of primary Sjogren syndrome is unknown, whereas secondary Sjogren syndrome is associated with underlying autoimmune diseases (e.g., rheumatoid arthritis). As the immune system mainly attacks lacrimal and salivary glands, patients typically present with  xerophthalmia  (dry eyes) and  xerostomia (dry mouth), the combination of which is also known as  sicca syndrome. The disease may also involve the skin, joints, internal organs, and nervous system .

28. Epidemiology Sex : ♀ > ♂ (∼ 9:1) Age of onset: typically 40–60 years

29. Etiology Primary Sjogren syndrome : idiopathic (association with  HLA-DR52  estimated in 87% of cases) Secondary Sjogren syndrome Autoimmune connective tissue diseases: rheumatoid arthritis, systemic lupus erythematosus , systemic sclerosis,  polymyositis Primary biliary cirrhosis (PBC)

30. Clinical features Glandular symptoms Inflammation of the salivary glands : decreased production of saliva →  xerostomia  (dry mouth) Dysphagia Increased formation of  dental caries  and tendency to oral infections  Parotitis Inflammation of the  lacrimal glands  (chronic dacryoadenitis ): decreased secretion of tears →  xerophthalmia  (dry eyes)  →  keratoconjunctivitis sicca Redness, itching, burning of eyes Sensation of sand or foreign body in the eyes Blurred vision Sicca syndrome : combination of  dry mouth  and  dry eyes Nasal dryness → chronic rhinitis, nosebleeds Pharyngeal, tracheal, and bronchial dryness → persistent, dry cough Vaginal dryness →  dyspareunia  (painful intercourse) and increased risk of infections

31. Extraglandular symptoms General symptoms : fatigue and  arthralgias  (∼ 70% of cases) Skin manifestations :  xerosis  ;  Raynaud's phenomenon  (∼ 15–30% of cases) Vasculitis   (∼ 10% of cases) Palpable  purpura  of the legs Recurrent  urticaria , skin ulcerations Glomerulonephritis Neurological and psychiatric manifestations Depression Variety of focal and/or diffuse findings (e.g., impaired gross motor control, paresis, seizures, peripheral neuropathy) Gastrointestinal manifestations : e.g., dyspepsia, reflux  esophagitis

32. Mixed connective tissue disease (Sharp's syndrome) Definition : overlapping symptoms of systemic sclerosis, systemic lupus erythematosus  (SLE), and  polymyositis Clinical presentation Myositis Arthritis Acrosclerosis Raynaud's phenomenon Pulmonary hypertension The course is usually milder than that of other connective tissue diseases (CTD), but may progress into another CTD.