STEPTRACKERBIOCHEMISTRY + PATHOLOGY + GENETICS | CELL BIOLOGY | HIGH-YIELD REVIEW

Elastin, Fibrillin & Connective Tissue Disorders

Elastic tissue stretches and recoils — break its scaffold (fibrillin) or let elastase run free and the aorta, lens and lungs pay.

FOCUS ON
Elastin is rich in nonhydroxylated proline, glycine and lysine; cross-linked by lysyl oxidase (desmosine). Fibrillin-1 is its scaffold — mutated in Marfan (↑ TGF-β). α1-Antitrypsin stops elastase — deficiency → panacinar emphysema + liver disease. Homocystinuria mimics Marfan but has intellectual disability, clots and a downward lens. Wrinkles = ↓ collagen and elastin (sun, age).
PROTEIN · DISORDER
MECHANISM
FEATURES
CLUE
Elastin
Stretchy protein in lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava; tropoelastin cross-linked by lysyl oxidase (desmosine, isodesmosine)
Recoil after stretch
Degraded by elastase
Fibrillin-1
Glycoprotein forming microfibrils that scaffold elastin; regulates TGF-β
—
FBN1 on chromosome 15
Marfan syndrome
AD · FBN1
Defective fibrillin → weak elastic tissue, excess TGF-β signaling
Tall, long limbs, arachnodactyly, hypermobility, pectus, lens up and out, MVP, aortic root dilation → dissection
β-blockers, losartan; cystic medial degeneration
Homocystinuria
AR · cystathionine β-synthase
↑ Homocysteine damages vessels and connective tissue
Marfanoid habitus, lens down and in, intellectual disability, osteoporosis, arterial and venous thrombosis
Details in 9.04
Loeys-Dietz syndrome
AD · TGF-β receptor
↑ TGF-β signaling
Aggressive aortic aneurysms, bifid uvula, hypertelorism, arterial tortuosity
Dissection at small diameters
α1-Antitrypsin deficiency
codominant · SERPINA1
Lack of elastase inhibitor in lung; misfolded PiZ protein retained in hepatocyte ER
Panacinar emphysema (lower lobes, young, worse with smoking) + cirrhosis; PAS⁺ globules in liver
PiZZ genotype most severe
Williams syndrome (contrast)
7q11.23 deletion
Includes the elastin gene
Supravalvular aortic stenosis, elfin face, friendliness, hypercalcemia
See 5.08
Cutis laxa
Elastin/fibulin defects
Loose, sagging, inelastic skin; emphysema, hernias
Skin hangs in folds (not hyperextensible like EDS)
Photoaging & wrinkles
UV → ↑ collagenases, ↓ collagen synthesis, abnormal elastin (solar elastosis)
Wrinkled, leathery skin
Retinoids ↑ collagen synthesis

Mechanism — elastase vs its inhibitor

Neutrophils, macrophagesRelease elastase
→
α1-AntitrypsinNeutralizes it
→
Elastic alveolar walls intact
A1AT ↓ or smoking(oxidants inactivate A1AT)
→
Unopposed elastase
→
Alveolar walls destroyedEmphysema

Marfan vs homocystinuria

FEATURE
MARFAN
HOMOCYSTINURIA
Inheritance
AD
AR
Lens
Up and out
Down and in
Intellect
Normal
Often impaired
Thrombosis
No
Yes
Lethal threat
Aortic dissection
Stroke, MI, VTE

How it's tested

COMMON CONFUSIONA tall patient with ectopic lenses: up-and-out with normal IQ = Marfan; down-and-in with clots and low IQ = homocystinuria.
THE TRAPα1-Antitrypsin deficiency causes panacinar emphysema in the lower lobes; smoking-related emphysema is centriacinar and upper-lobe.
YOUR APPROACHLook at lens direction, aorta, clotting and IQ for the tall patient; for emphysema, check age, smoking and lobe.

If you see… think…

Tall, arachnodactyly, lens up and out, aortic root dilation → Marfan (FBN1)
Marfanoid habitus + lens down and in + DVT → homocystinuria
Young nonsmoker with basal emphysema and cirrhosis → α1-antitrypsin deficiency
PAS⁺ globules in hepatocytes → A1AT (PiZ) retention
Bifid uvula + aortic aneurysm → Loeys-Dietz
Supravalvular aortic stenosis, elfin face → Williams (elastin gene deletion)
Cross-links unique to elastin → desmosine
Aortic histology in Marfan → cystic medial degeneration
Loose, sagging skin that doesn't snap back → cutis laxa
Overactive signaling pathway in Marfan → TGF-β