Connective tissue disorders Notes

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 osms.it/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) osms.it/ehlers-danlos_syndrome 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 osmosis.org/learn/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