Case Scenario 1:
A 2-year-old child is brought to the pediatrician due to suspected child abuse. On examination, the child has blue sclerae, hearing loss in both ears, and multiple long bone fractures (both recent and healing).
- What is the most probable diagnosis?
- Describe the structure of the defective molecule involved in this condition.
Answer:
- Probable Diagnosis: The most probable diagnosis is Osteogenesis Imperfecta (OI), also known as brittle bone disease.
Defective Molecule: Type I Collagen
Osteogenesis Imperfecta is most commonly caused by a genetic defect in Type I collagen, which is a major structural protein in bone, skin, sclera, tendons, and ligaments.
Structure of Type I Collagen:
- Type I collagen is a triple helical protein composed of:
- Two α1 chains (COL1A1 gene)
- One α2 chain (COL1A2 gene)
- These chains are rich in the amino acids:
- Glycine – at every third position, critical for tight helical packing
- Proline and Hydroxyproline – help in helix stability
- The three chains are synthesized as preprocollagen in fibroblasts, then processed to procollagen, and finally assembled into collagen fibrils outside the cell.
Defect in OI:
- Mutations in COL1A1 or COL1A2 genes cause:
- Reduced production (quantitative defect) or
- Abnormal structure (qualitative defect) of Type I collagen.
This leads to bone fragility, blue sclerae, hearing loss (due to ossicle defects), and other connective tissue abnormalities.
Case Scenario 2:
A 25-year-old male presents to the clinic with complaints of frequent joint dislocations, hyperextensible skin, and delayed wound healing. On examination, his skin appears soft and velvety with a doughy texture. The clinician suspects a connective tissue disorder affecting structural integrity due to defective extracellular matrix components.
- a) Describe the composition and major functions of the extracellular matrix (ECM).
b) Explain how abnormalities in ECM components can lead to clinical features seen in this patient.
Answer:
- a) Composition and major functions of the extracellular matrix (ECM):
Composition:
The extracellular matrix is a complex network of macromolecules secreted by cells that provide structural and biochemical support to surrounding cells. It is primarily composed of:
- Fibrous proteins:
- Collagen: Provides tensile strength; most abundant ECM protein.
- Elastin: Provides elasticity and resilience to tissues.
- Proteoglycans:
- Core proteins covalently attached to glycosaminoglycans (GAGs) like hyaluronic acid, chondroitin sulfate.
- Provide hydration and resistance to compressive forces.
- Glycoproteins (adhesive proteins):
- Examples: Fibronectin, laminin, entactin.
- Mediate cell-ECM adhesion and migration.
- Basement membrane:
- Specialized ECM that supports epithelial and endothelial cells.
- Composed of type IV collagen, laminin, and heparan sulfate proteoglycans.
Functions:
- Provides structural support to tissues and organs.
- Regulates cell adhesion, migration, proliferation, and differentiation.
- Acts as a reservoir for growth factors.
- Plays a key role in tissue repair and development.
- Involved in cell signaling via integrins and other ECM receptors.
- b)
The patient’s symptoms — joint hypermobility, skin hyperextensibility, and poor wound healing — suggest an underlying defect in collagen, a key structural protein in the ECM.
These clinical features are characteristic of Ehlers-Danlos Syndrome (EDS), a group of connective tissue disorders caused by defective collagen synthesis, structure, or processing.
- Joint hypermobility occurs due to weakened ligaments and joint capsules, which are rich in collagen. Abnormal collagen fibers fail to provide proper tensile strength and stability.
- Hyperextensible skin results from defective dermal collagen, making skin more elastic and fragile.
- Delayed wound healing and easy bruising are due to impaired cross-linking and structural integrity of collagen in the skin and blood vessels.
In summary, abnormalities in ECM components, especially collagen types I, III, and V, disrupt tissue integrity and mechanical support, leading to the clinical manifestations observed.
Case Scenario 3:
A child is brought to the pediatrics department by the parents with a history of passing blood in urine (hematuria). After clinical evaluation and relevant investigations, the child is diagnosed with Alport Syndrome.
- a) Name the extracellular matrix molecule that is defective in this condition.
- b) Describe the structure and composition of the glomerular basement membrane (GBM) and its relevance to the extracellular matrix.
Answer:
- The defective molecule in Alport Syndrome is Type IV Collagen.
- Specifically, the α3, α4, or α5 chains of type IV collagen are affected, depending on the genetic subtype.
- These chains are essential components of the glomerular basement membrane (GBM) in the kidney.
- b) Structure and composition of the glomerular basement membrane (GBM) and its relevance to the extracellular matrix:
The glomerular basement membrane (GBM) is a specialized extracellular matrix (ECM) component that plays a critical role in the filtration barrier of the kidney.
Structure and Layers:
- The GBM lies between the glomerular endothelial cells and podocytes.
- It is formed by the fusion of the basal laminae of these two cell types.
Composition:
The main components of the GBM include:
- Type IV collagen (especially α3, α4, α5 chains): Provides structural integrity.
- Laminin: Important for cell adhesion and signaling.
- Nidogen (entactin) and heparan sulfate proteoglycans (e.g., agrin): Contribute to charge selectivity and structural stability.
Case Scenario 4:
A 10-year-old child is brought to the outpatient department by parents due to concerns about unusual physical features. On physical examination, the child has long slender fingers (arachnodactyly), lens dislocation, joint hypermobility, and signs of an aortic aneurysm. Based on the clinical findings, a probable diagnosis of Marfan’s Syndrome is made.
- a) Name the extracellular matrix molecule that is defective in the above case.
b) Mention one other disease associated with a defect in the same molecule.
c) Enumerate any three functions of this molecule.
Answer:
- a) Name the extracellular matrix molecule that is defective in the above case.
The defective molecule is Fibrillin-1.
- It is encoded by the FBN1 gene.
- Fibrillin-1 is an important glycoprotein of the extracellular matrix involved in the formation of microfibrils.
- b) Another disease associated with a defect in the same molecule is:
- Weill–Marchesani Syndrome (WMS) – Type 2 (autosomal dominant form)
This form can also be caused by mutations in the FBN1 gene, though it presents with short stature, brachydactyly, and lens dislocation — features opposite to Marfan’s syndrome.
- c) Three functions of Fibrillin-1:
- Structural support:
- Forms microfibrils that provide strength and elasticity to connective tissues such as ligaments, skin, and blood vessels.
- Elastic fiber formation:
- Acts as a scaffold for the deposition of elastin, contributing to elastic properties of tissues.
- Regulation of growth factors:
- Sequesters and regulates transforming growth factor-beta (TGF-β), thereby influencing cell growth, differentiation, and ECM remodeling.
Case Scenario 5:
A 5-year-old child is brought to the pediatrician with loose skin, a soft, doughy texture, and a history of delayed wound healing. On examination, the child has joint hypermobility, visible skin folds, and a hoarse voice. The doctor suspects a rare connective tissue disorder involving abnormal elastic fibers, possibly Cutis Laxa.
- a) Name the extracellular matrix protein that is likely defective in this condition.
b) Describe the structure and functions of this protein in the extracellular matrix.
c) What are the consequences of elastin defects in connective tissue, and how do they relate to the symptoms in this case?
Answer:
- a) The defective protein is Elastin.
- It is the key protein responsible for the elastic properties of connective tissues such as skin, lungs, and blood vessels.
- b) Structure:
- Elastin is a highly hydrophobic protein rich in glycine, valine, alanine, and proline.
- It is synthesized as a soluble precursor called tropoelastin.
- Tropoelastin is secreted into the extracellular space and cross-linked by the enzyme lysyl oxidase to form insoluble elastin fibers.
- Elastin is embedded within a scaffold of microfibrils, primarily composed of fibrillin-1.
Functions:
- Provides elasticity and recoil:
- Especially important in skin, lungs, arteries, ligaments, and bladder.
- Allows tissues to stretch and return to original shape:
- Vital in organs subjected to repeated stretching (e.g., lungs during breathing, arteries during blood flow).
- Maintains structural integrity:
- Supports connective tissue resilience while preserving flexibility.
- c) What are the consequences of elastin defects in connective tissue, and how do they relate to the symptoms in this case?
Defective elastin or abnormal elastin cross-linking leads to loss of tissue elasticity, resulting in clinical features such as:
- Loose, sagging skin (Cutis Laxa):
- Skin lacks recoil and hangs in folds due to reduced elastin content.
- Joint hypermobility:
- Ligaments and joint capsules lose elastic support, leading to excessive joint movement.
- Hoarse voice:
- Elastic fiber loss in vocal cords causes changes in voice quality.
- Pulmonary and cardiovascular complications (in severe forms):
- Lungs lose elastic recoil → emphysema
- Weak arterial walls → aneurysms or arterial tortuosity
Thus, the symptoms in this child (loose skin, joint laxity, hoarseness) are directly related to defective elastin, an essential component of the extracellular matrix in elastic tissues
Case Scenario 6:
A 3-year-old child is brought to the pediatric clinic with a history of developmental delay, coarse facial features, joint stiffness, and enlarged liver and spleen. Urine examination reveals the presence of excess dermatan sulfate and heparan sulfate. Based on clinical and laboratory findings, a diagnosis of a mucopolysaccharidosis (MPS), a disorder involving defective degradation of glycosaminoglycans (GAGs), is made.
- a) What are glycosaminoglycans? Mention their major types.
b) Describe the structure and functions of glycosaminoglycans in the extracellular matrix.
c) How does defective metabolism of GAGs lead to clinical features in this case?
Answer:
- a) Definition:
Glycosaminoglycans (GAGs), also known as mucopolysaccharides, are long, unbranched polysaccharide chains composed of repeating disaccharide units. Each unit typically consists of an amino sugar (like N-acetylglucosamine or N-acetylgalactosamine) and a uronic acid (like glucuronic acid or iduronic acid).
They are negatively charged, highly hydrophilic, and found abundantly in the extracellular matrix, often attached to proteins to form proteoglycans.
Major Types of GAGs:
- Hyaluronic acid
- Chondroitin sulfate
- Dermatan sulfate
- Heparan sulfate
- Heparin
- Keratan sulfate
- b) Structure:
- GAGs consist of repeating disaccharide units, with one sugar being an amino sugar and the other a uronic acid.
- Most GAGs (except hyaluronic acid) are sulfated and bound to a core protein, forming proteoglycans.
- Due to high negative charge, they attract water and cations, especially sodium ions.
Functions:
- Hydration and resistance to compression:
- GAGs form gel-like matrices that resist compressive forces (e.g., in cartilage and intervertebral discs).
- Support and spacing:
- Maintain extracellular spacing and tissue turgidity.
- Cell signaling and migration:
- Interact with growth factors and cell receptors, influencing cell proliferation and movement.
- Lubrication:
- In joints, hyaluronic acid contributes to synovial fluid viscosity, aiding in lubrication.
- Filtration:
- Heparan sulfate in the glomerular basement membrane helps in charge-selective filtration in the kidney.
c)In conditions like mucopolysaccharidoses (e.g., Hurler, Hunter syndromes), there is a deficiency of lysosomal enzymes required to degrade specific GAGs.
Consequences:
- Accumulation of undegraded GAGs:
- Leads to storage in lysosomes of cells across various tissues.
- Multisystem involvement:
- Hepatosplenomegaly due to storage in liver and spleen
- Coarse facial features from dermal and bone involvement
- Joint stiffness due to GAG buildup in connective tissues
- Developmental delay from CNS accumulation (in some forms)
- Excretion in urine:
- Excess GAGs like dermatan sulfate and heparan sulfate are excreted and can be detected in urine tests.
Thus, defective breakdown of GAGs disrupts normal extracellular matrix turnover, leading to progressive tissue and organ dysfunction.