Collagen Disorders😍

Marfan Syndrome

Q. A 15-year-old boy presented to the Ophthalmology department with an acute reduction in visual acuity in both the eyes. The direct observation of both the eyes is shown here. The ophthalmologist suspected a disorder and ordered for genetic testing, which revealed FBN1 gene mutation. Which of the following is true about the disorder and the protein involved?

• A. The protein reduces TFG-Beta levels

• B. Alpha 2 agonists delay the progression of the disorder

• C. It is an autosomal recessive disorder

• D. The protein involved reduces the elasticity of tissues normally

• Autosomal dominant condition.

• Chromosome affected: 
• Chromosome 15

• Gene affected: 
• FBN1 gene (Fibrillin 1 gene defect)

Fibrillin protein:

• Forms microfibrils in connective tissue.

• Normally reduces TGF beta levels
• TGF β causes necrosis

• With elastin:
• forming scaffolding for elastin
• Increases elasticity
• In Lungs

• Without elastin:
• Increases tensile strength
• In Bone, Tendon, Suspensory Ligament of Linn (Eyes)

Pathophysiology:

• Fibrillin protein ↓↓
• Elasticity, tensile strength ↓↓
• ↑↑ TGF β

• Loss of elasticity:
• Lung gets expanded
• Lung bullae and pneumothorax.
• root of blood vessels.
• Aortic regurgitation and mitral valve prolapse.

• Increased TGF beta levels cause:
• Cystic medial necrosis.
• Dissection of the aorta.

• Loss of tensile strength causes:
• Arachnodactyly
• B/L superotemporal dislocation of the lens.

Clinical Features:

• Mnemonic: MARFANS
• M: Mitral valve prolapse 
• most common cardiac abnormality
• A: Aortic dissection 
• most common cause of death
• R: Retinal detachment
• F: Freely movable joints 
• most common joint: thumb joint
• A: Arachnodactyly 
• (spider-like long fingers, thumb coming out of palm); 
• High arched palate
• N: Nine feet tall (very tall individuals)
• S: Syndrome
• If "disease":
• Dislocation of the lens (Ectopia lentis)
• Direction: Superotemporal (upward and outward)
• Mnemonic: "fan is up, air goes out"
• Differential (opposite dislocation): 
• Homocystinuria (inferonasal)
• If "syndrome":
• Sternal deformity / Pigeon chested individuals

• Cardiovascular:
• Cystic medial necrosis of the aorta
• Aortic root aneurysm, rupture, or dissection
• Most common cause of death
• Mitral valve prolapse

• Lung:
• ↑ Risk of spontaneous pneumothorax

• Overall most common abnormality: 
• Skeletal abnormality 

• Specific Signs:
• Steinberg sign:
• Thumb coming out when folded in fist
• Mnemonic: Stain → Stick ur thumb out and stain it
• Walker sign:
• Little finger and thumb can hold the wrist
• Mnemonic: Walk around the wrist

Revised Gent Criteria: Marfan Gentleman

1. Family history (autosomal dominant)

2. Clinical features 

3. Fibrillin 1 gene mutation

Management:

• Beta blockers or losartan
• reduce TGF beta levels.

Exceptions → Penetrance: 

• The percentage of individuals with a given genotype who express the associated phenotype.
• Example calculation:
• If 70 out of 100 people with the specific genotype are diseased,
• the penetrance is 70%.

Extracellular Events:

Types and Associated Conditions: SCAB

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Sweet stain

• Stain Reticulin fibres of liver
• Type 3 collagen

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Type IV Collagen Pathologies

Disorder	Chr	Gene/Target	Pattern
Goodpasture	2	• Anti GBM antibody • Type 1 RPGN • Type 2 Hypersensitivity • α3 chain of Type 4 collagen (COL4A3)	Linear IF
Thin BM disease	2	• COL4A4 • Benign familial Hematuria	ㅤ
Alport	XLD	• COL4A5 >> COL4A3/4 (AR/AD) Triad 1. SNHL 2. Hematuria 3. Anterior Lenticonus	Basket weave pattern

Important Information

• The most common mode of inheritance in osteogenesis imperfecta:
• AD.

• genetically abnormal collagen (Type I collagen defect).
• Leads to weak bones and recurrent pathological fractures.

• Type 2 is most severe

• Defects in COL1A1 or COL1A2
  (type I collagen).

Clinical Features

• Mnemonic: BITE
• Bones = fractures
• I = blue sclerae
• Teeth = imperfections
• Ear = hearing loss

• Triad:
1. Blue sclera.



• thin sclera → Choroid visible
2. Limb deformities due to recurrent fractures.
3. Deafness.

• Easy bruising.

• Multiple fractures in different stages of healing.
• On antenatal scans.
• Deformities

• Delayed dentition.

• Dental imperfections
• (dentinogenesis imperfecta → opalescent teeth that wear easily due to lack of dentin)

• Hearing loss (abnormal ossicles)

Labs

• Normal lab values.

Treatment

• Treat with bisphosphonates to ↓ fracture risk.
• Pamidronate.

• Mnemonic: Pavam koch → Pamidronate

NOTE:

• Vander Hoeve Syndrome:
• Osteogenesis Imperfecta.
• Blue sclera.
• Otosclerosis.
• Pregnant() female on shorts (Schwartz sign) vandering (Vander) in Car (Carharts), Oto (Otosclerosis) van Van (Vander)- para (Paracusis willisii)vach - bcz avalde bone(Excessive bone deposition) poyi

• ATP Genes
1. ATP 7A → Menkes
2. ATP 7B → Wilsons
3. ATP → Rotor syndrome
• [DR → (DJ syndrome, Rotor syndrome)→ need MRP and ATP]

• Chromosome 17
• Newly 17 (NF1) yr girl tried bra for 1st (BRCA1) time
• Police caught At 17 → 17p13q → p53

• Chromosome 13
• RB gene, BRCA 2, ATP 7B
• all Betas

Argininosuccinic Aciduria

Trichorrhexis nodosa (brittle hair)

• Enzyme deficient:
• Arginosuccinate lyase

• Also caused by
• Menke’s kinky hair
• Hypothyroidism
• Iron deficiency

• Mnemonic: Manka () was Iron () and thyroid deficent ()
• Urge (Arginosuccinate lyase) to pull hair

General Clinical Features

• Encephalopathy

• Respiratory alkalosis

• Tachypnoea

• Hyperammonemia + ↑ plasma glutamine

Neonates:

• feeding difficulties,

• failure to thrive,

• lethargy,

• convulsions, coma

NOTE: NETHERTON SYNDROME

• Netherland → Bamboo (Bamboo hair), Fish (Icthyosis), Spin (SPINK)

Epidermolysis Bullosa (EB)

• Meaning: Epidermis and formation of bulla

• Also called: Mechanobullous disorder

• Bullae form on mechanical trauma

1. Neonatal pemphigus

2. Epidermolysis bullosa

3. Congenital syphilis

4. Chronic bullous disease of childhood

Types:

• Congenital (3 types):
1. EB Simplex (EBS)
2. Junctionalis
3. Dystrophic

• Acquired (EB acquisita):
• Antibodies against collagen 7
• Leads to subepidermal disorder

Congenital EB

• Categorized by defect location:

• Mechanism:
• Gene defect → structural defect → skin split (no autoantibody formation)

• Presentation:
• Early in life
• Skin splits upon handling or massage
• At site of mechanical force or trauma

• Diagnosis:
• Skin biopsy: Intra- or subepidermal split
• Diagnostic test: Electron microscopy
• DIF: Not performed (no antibody formation, so no fluorescence)

• Treatment:
• Gene therapy (only treatment available)