Connective tissue disorders Notes


Osmosis High-Yield Notes

This Osmosis High-Yield Note provides an overview of Connective tissue disorders essentials. All Osmosis Notes are clearly laid-out and contain striking images, tables, and diagrams to help visual learners understand complex topics quickly and efficiently. Find more information about Connective tissue disorders:

Alport syndrome

Ehlers-Danlos syndrome

Marfan syndrome

NOTES NOTES CONNECTIVE TISSUE DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Genetic disorders affecting synthesis of connective tissue components (e.g. fibrillin, collagen) ▪ Genetic mutation → dysfunctional protein (e.g. ↓ function fibrillin/collagen) → ↓ supportive function connective tissue → ↓ function of various organs, tissues ▪ Common disorders ▫ Marfan syndrome (fibrillin 1 mutation) ▫ Ehler–Danlos syndrome (various etiologies) ▫ Osteogenesis imperfecta (collagen Type I mutation) ▫ Alport syndrome (collagen Type IV mutation) ▪ Vary from dominant to recessive, range in severity 152 OSMOSIS.ORG SIGNS & SYMPTOMS ▪ May affect all organ systems containing connective tissue; esp. musculoskeletal, ocular, cardiovascular systems DIAGNOSIS OTHER DIAGNOSTICS ▪ Standardized criteria ▪ Genetic testing (confirmation) TREATMENT OTHER INTERVENTIONS ▪ Supportive due to the genetic basis of disease, not curable
Chapter 23 Connective Tissue Disorders ALPORT SYNDROME PATHOLOGY & CAUSES ▪ Rare disorder caused by mutations in genes encoding for chains of Type IV collagen → abnormal basement membranes of kidney glomerulus, eye, cochlea ▫ AKA hereditary nephritis ▪ Mutation substitutes glycine with different amino acid → triple-helix unable to form → impaired basement membrane structure ▫ Glomerular basement membrane progressively hardens as abnormal Type IV collagen accumulates → thin glomerular basement membrane nephropathy ▫ Impaired ability of hair cells attached to basement membrane in organ of Corti (in cochlea) to generate nerve signals ▫ Thinning of lens capsule → disruption of lens shape → anterior lenticonus TYPES X-linked ▪ COL4A5 on X-chromosome ▪ Presents early, most common form Autosomal recessive/dominant ▪ COL4A3, COL4A4 mutations Thin basement membrane nephropathy ▪ Mild mutations in COL4A3, COL4A5 ▪ Microscopic hematuria (sole symptom) RISK FACTORS ▪ Family history COMPLICATIONS ▪ End-stage renal disease, sensorineural hearing loss, changes in visual acuity, aortic aneurysms SIGNS & SYMPTOMS ▪ Generally appear in early childhood/ adolescence ▪ Renal ▫ Progressive renal insufficiency, hypertension ▪ Eye ▫ Corneal abrasions, lens opacity, ocular pain ▪ Ear ▫ Initial high-frequency hearing loss → loss of normal speech DIAGNOSIS LAB RESULTS Urinalysis ▪ Hematuria, proteinuria, ↑ creatinine OTHER DIAGNOSTICS Clinical exam ▪ Renal failure with deafness, with no other apparent cause Ophthalmic examination ▪ Slit lamp examination of eye ▫ “Oil droplet” reflex ▪ Fundoscopy ▫ White/yellow granulations in retina (fleck retinopathy) Kidney/skin biopsy (confirmation) ▪ Immunohistochemistry (labelled antibody applied to biopsy, viewed on slide) ▫ Label usually identifies collagen alpha chains ▫ Misfolded collagen degraded; does not stain OSMOSIS.ORG 153
▪ Electron microscopy ▫ Early disease: thinning of glomerular basement membrane ▫ Later disease: glomerular basement membrane thin, thick, abnormal segments, split lamina densa (appears as woven basket) Gene testing ▪ Gene testing for COL4A genes ▫ Diagnostic procedure of choice due to noninvasive nature, accuracy TREATMENT MEDICATIONS ▪ Renal ▫ Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers prevent progression to kidney failure, dialysis, kidney transplant SURGERY ▪ Anterior lenticonus ▫ Replacement of lens OTHER INTERVENTIONS ▪ Hearing loss may benefit from hearing aids EHLERS–DANLOS SYNDROME (EDS) PATHOLOGY & CAUSES ▪ Defective collagen synthesis → group of rare connective tissue disorders → tissue fragility ▫ Single gene disorders ▫ Autosomal dominant/recessive ▫ 30 types of collagen may be affected ▫ 13 different Ehler–Danlos syndromes classified on distribution of tissue involvement CAUSES ▪ Gene mutation (specific gene varies depending on type) → defective fibrous proteins/enzymes → ↑ elasticity of tissues, structure, ↓ strength of tissues ▪ Minor injuries → gaping defects → repair difficult due to low tensile strength RISK FACTORS ▪ Family history 154 OSMOSIS.ORG COMPLICATIONS ▪ Colon, large artery, corneal rupture; retinal detachment, diaphragmatic hernias, premature arthritis; pregnancy complications (e.g. cervical insufficiency, premature rupture of membranes) SIGNS & SYMPTOMS ▪ Skin ▫ Hyperextensive, fragile, vulnerable to trauma; easy bruising; atrophic scars ▪ Ligament laxity ▫ Hypermobile joints; joint dislocation predisposition (diagnosed by Beighton hypermobility scale); spinal malformations (e.g. scoliosis); osteochondrosis, arthritis; pain in muscles, joints ▪ Bones, joints ▫ Pes planus, pectus excavatum, high arched palate; islocations ▪ Cardiovascular
Chapter 23 Connective Tissue Disorders ▫ Spontaneous artery dissection; valvular disorders; arterial rupture; Raynaud’s phenomenon; impaired platelet aggregation ▪ Spontaneous organ rupture ▪ Cerebrovascular rupture DIAGNOSIS OTHER DIAGNOSTICS ▪ Clinical exam ▫ Typical presentation (e.g. lens dislocation, cardiovascular incidents, hypermobility) ▫ Beighton score (evaluates hypermobility): nine criteria, four needed to establish hypermobility ▪ Ehler–Danlos specific genetic panel (confirmation) ▪ Skin biopsy TREATMENT MEDICATIONS ▪ According to type ▫ Pain medication: nonsteroidal antiinflammatory drugs (NSAIDs) for arthralgia, myalgia SURGERY ▪ According to type ▫ Joint surgery for severe arthritis OTHER INTERVENTIONS ▪ According to type ▫ Education, counseling ▫ Physical therapy to prevent joint damage ▫ Casting/orthoses to stabilize joints ▫ Regular cardiovascular monitoring Figure 23.1 Hypermobility at the wrist and metacarpophalangeal joints in an individual with Ehlers–Danlos syndrome. OSMOSIS.ORG 155
MARFAN SYNDROME PATHOLOGY & CAUSES ▪ Genetic disorder of defective connective tissue CAUSES ▪ Fibrillin 1 structural protein dysfunction due to FBN1 gene mutation (locus 15q21) ▫ Autosomal dominant ▫ Compromised extracellular matrix (e.g. elastic fibers) ▫ Fibrillin loss → ↑ transforming growth factor beta (TGF-β) → ↓ vascular muscle, extracellular matrix → compromises strength, elasticity → Marfanoid appearance ▪ Skeleton, heart, blood vessels, eyes, lungs; most commonly affects aorta, ligaments, ciliary zonules supporting lens ▪ Hyperextensibility with inability to extend elbows 180º ▪ Scoliosis ▪ Pes excavatum, pigeon chest ▪ Arachnodactyly (long fingers) ▫ Thumb sign: thumb protrudes beyond ulnar margin when fist clenched ▫ Wrist sign: entire fingernail of fifth finger covered by thumb when wrapped around wrist ▪ Dolichocephaly ▫ Narrow skull RISK FACTORS ▪ Family history COMPLICATIONS ▪ Lens dislocation, aortic rupture, pneumothorax SIGNS & SYMPTOMS ▪ Vary in severity, rarely present at birth (neonatal Marfan syndrome) Eyes ▪ Bilateral cranial, temporal dislocation of lens (ectopia lentis); highly specific ▪ Retinal detachment ▪ Downward slant of palpebral fissures Skeleton ▪ Tall, slim with long (↑ arm span to height ratio); slender limbs ▪ Narrow, arched palate 156 OSMOSIS.ORG Figure 23.2 An adolescent female with Marfan syndrome. She is taller than average and thin, with long arms and legs. Arachnodactyly is also seen. Heart ▪ Aortic root dilation, floppy valve syndrome (mitral valve), aortic dilation causes aortic valve insufficiency Lungs ▪ Blebs, bullae (dilated spaces filled with air predisposing to spontaneous pneumothorax)
Chapter 23 Connective Tissue Disorders Blood vessels ▪ Cystic medial necrosis of aorta, aortic incompetence, dissecting aortic aneurysms Skin ▪ Striae (stretch marks) DIAGNOSIS OTHER DIAGNOSTICS ▪ History, physical exam ▫ Ghent nosology criteria: scale using major, minor indicators to establish Marfan diagnosis, max 20 points; includes family history, skeletal, vascular, ocular, pulmonary/skin symptoms (e.g. ectopic lens and aortic dissection) ▪ Genetic testing ▫ Confirmation of FBN1 mutation TREATMENT MEDICATIONS ▪ Beta blockers (slow aortic dilation) ▪ Angiotensin receptor blockers (decrease TGF-β signalling, slow aortic dilation) SURGERY ▪ Valve, lens replacement; aortic dissection repair OTHER INTERVENTIONS ▪ Physiotherapy ▫ Restrict high-intensity exercise, scoliosis treatment ▪ Routine aortic, heart, ophthalmic screening Figure 23.3 A contrast CT scan of the chest in the sagittal plane demonstrating aortic root dilation in an individual with Marfan syndrome. OSMOSIS.ORG 157

Osmosis High-Yield Notes

This Osmosis High-Yield Note provides an overview of Connective tissue disorders essentials. All Osmosis Notes are clearly laid-out and contain striking images, tables, and diagrams to help visual learners understand complex topics quickly and efficiently. Find more information about Connective tissue disorders by visiting the associated Learn Page.