Abnormalities in chromosome number
Trisomy 21 (Down syndrome)
(1) The most common chromosomal disorder.
(2) A disorder affecting autosomes. It is generally caused by meiotic nondisjunction in the mother, which results in an extra copy of chromosome 21 or trisomy 21.
(3) Risk increases with maternal age.
(4) Clinical findings include mental retardation and congenital heart defects. There is also an increased risk of developing acute leukemia
and an increased susceptibility to severe infections.
(5) Oral findings include macroglossia, delayed eruption of teeth, and hypodontia.

Trisomies 18 and 13
(1) Trisomy 18 (Edwards syndrome):
characterized by an extra copy of chromosome 18. Oral findings include micrognathia.
(2) Trisomy 13 (Patau’s syndrome): characterized by an extra copy of chromosome 13. Oral findings include cleft lip and palate.
(3) Meiotic nondisjunction is usually the cause of an extra chromosome in both of these trisomies.
(4) Clinical findings for both of these trisomies are usually more severe than trisomy 21. Most children with these diseases die within months after being born due to manifestations such as congenital heart disease.

Klinefelter’s syndrome
(1) One of the most common causes of male hypogonadism.
(2) Characterized by two or more X chromosomes and one or more Y chromosomes. Typically, there are 47  chromosomes with the karyotype of XXY.
(3) The cause is usually from meiotic nondisjunction.
(4) Clinical findings include atrophic and underdeveloped testes, gynecomastia, tall stature, and a lower IQ.

Turner’s syndrome
(1) One of the most important causes of amenorrhea.
(2) Characterized by having only one X chromosome, with a total of 45 chromosomes and a karyotype of XO.
(3) Clinical findings include underdeveloped female genitalia, short stature, webbed neck, and amenorrhea. Affected females are usually
sterile. Unlike other chromosomal disorders, this one is usually not complicated by mental retardation.

Treacher Collins syndrome (mandibulofacial dysostosis)
(1) Genetic transmission: autosomal dominant.
(2) A relatively rare disease that results from abnormal development of derivatives from the first and second branchial arches.
(3) Clinical findings include underdeveloped zygomas and mandible and deformed ears. Oral findings include cleft palate and small or absent parotid glands.

DIABETES MELLITUS 
a group of metabolic disorders sharing the common underlying characteristic of hyperglycemia.  
Diabetes is an important disease because
1. It is common (affects 7% of the population). 
2. It increases the risk of atherosclerotic coronary artery and cerebrovascular diseases.
3. It is a leading cause of 
   a. Chronic renal failure
   b. Adult-onset blindness
   c. Non traumatic lower extremity amputations (due to gangrene) 
     
Classification 
Diabetes is divided into two broad classes:
1. Type1 diabetes (10%): characterized by an absolute deficiency of insulin secretion caused by pancreatic βcell destruction, usually as a result of an autoimmune attack.

2. Type2 diabetes (80%): caused by a combination of peripheral resistance to insulin action and an inadequate secretion of insulin from the pancreatic β cells in response to elevated blood glucose levels. 

The long-term complications in kidneys, eyes, nerves, and blood vessels are the same in both types.

Pathogenesis
Type 1 diabetes is an autoimmune disease and as in all such diseases, genetic susceptibility and environmental influences play important roles in the pathogenesis. The islet destruction is caused primarily by T lymphocytes reacting against immunologic epitopes on the insulin hormone located within β-cell; this results in a reduction of β-cell mass. The reactive T cells include CD4+ T cells of the TH1 subset, which cause tissue injury by activating macrophages, and CD8+ cytotoxic T lymphocytes; these directly kill β cells and also secrete cytokines that activate further macrophages. The islets show cellular necrosis and lymphocytic infiltration (insulitis). Autoantibodies against a variety of β-cell antigens, including insulin are also detected in the blood and may also contribute to islet damage. 

Type 2 Diabetes Mellitus: the pathogenesis remains unsettled. Environmental influences, such as inactive life style and dietary habits that eventuates in obesity, clearly have a role. Nevertheless, genetic factors are even more important than in type 1 diabetes. Among first-degree relatives with type 2 diabetes the risk of developing the disease is 20% to 40%, as compared with 5% in the general population. 
The two metabolic defects that characterize type 2 diabetes are 1.  A decreased ability of peripheral tissues to respond to insulin (insulin resistance) and 2. β-cell dysfunction manifested as inadequate insulin secretion in the face of hyperglycemia. In most cases, insulin resistance is the primary event and is followed by increasing degrees of β-cell dysfunction.

Morphology of Diabetes and Its Late Complications

The important morphologic changes are related to the many late systemic complications of diabetes and thus are likely to be found in arteries (macrovascular disease), basement membranes of small vessels (microangiopathy), kidneys (diabetic nephropathy), retina (retinopathy), and nerves (neuropathy). These changes are seen in both type 1 and type 2 diabetes. 

The changes are divided into pancreatic & extrapancreatic 
A. Pancreatic changes are inconstant and are more commonly associated with type 1 than with type 2 diabetes.
One or more of the following alterations may be present.
1. Reduction in the number and size of islets
2. Leukocytic infiltration of the islets (insulitis) principally byT lymphocytes.  

3. Amyloid replacement of islets; which is seen in advanced stages

B. Extrapancreatic changes 

1. Diabetic macrovascular disease is reflected as accelerated atherosclerosis affecting the aorta and other large and medium-sized arteries including the coronaries. Myocardial infarction is the most common cause of death in diabetics. Gangrene of the lower limbs due to advanced vascular disease, is about 100 times more common in diabetics than in the general population. 
2. Hyaline arteriolosclerosis
 is the vascular lesion associated with hypertension. It is both more prevalent and more severe in diabetics than in nondiabetics, but it is not specific for diabetes and may be seen in elderly nondiabetics without hypertension.
3. Diabetic microangiopathy
 is one of the most consistent morphologic features of diabetes, which reflected morphologically as diffuse thickening of basement membranes. The thickening is most evident in the capillaries of the retina, renal glomeruli, and peripheral nerves. The thickened capillary basement membranes are associated with leakiness to plasma proteins. The microangiopathy underlies the development of diabetic nephropathy, retinopathy, and some forms of neuropathy.
4. Diabetic Nephropathy: renal failure is second only to myocardial infarction as a cause of death from diabetes.

Three lesions encountered are: 
1. Glomerular lesions
2. Renal vascular lesions, principally arteriolosclerosis; and
3. Pyelonephritis, including necrotizing papillitis.  

Glomerular lesions:  these include 
a. diffuse glomerular capillary basement membrane thickening
b. diffuse glomerular sclerosis : diffuse increase in mesangial matrix; always associated with the above.  
c. nodular glomerulosclerosis (Kimmelstiel-Wilson lesion) refers to a rounded deposits of a laminated matrix situated in the periphery of the glomerulus 

Pyelonephritis: both acute and chronic pyelonephritis are more common & more severe 

Ocular Complications of Diabetes: Visual impairment up to total blindness may occur in long-standing diabetes. The ocular involvement may take the form of 
a. retinopathy 
b. cataract formation
c. glaucoma 

In both forms of long-standing diabetes, cardiovascular events such as myocardial infarction, renal vascular insufficiency, and cerebrovascular accidents are the most common causes of mortality. Diabetic nephropathy is a leading cause of end-stage renal disease. By 20 years after diagnosis, more than 75% of type 1 diabetics and about 20% of type 2 diabetics with overt renal disease will develop end-stage renal disease, requiring dialysis or renal transplantation. 
Diabetics are plagued by an enhanced susceptibility to infections of the skin, as well as to tuberculosis, 
pneumonia, and pyelonephritis. Such infections cause the deaths of about 5% of diabetics. 

METAPLASIA

A reversible replacement of one type of adult tissue by another type of tissue. It is usually an adaptive substitution to a. cell type more suited to an environment, often at the cost of specialised function.

(1) Epithelial metaplasia:

• Squamous metaplasia. This is the commoner type of metaplasia and is seen in:
  • Tracheobronchial lining in chronic smokers and in bronchiectasis.
  • In Vitamin A deficiency.
• Columnar metaplasia:
  • Intestinalisation of gastric mucosa in chronic gastritis.

(2) Connective tissue metaplasia:

• Osseous-Metaplasia in :
  • Scars.
  • Myositis ossificans
• Myeloid metaplasia in liver and spleen.

FUNGAL INFECTION

Aspergillosis

Opportunistic infections caused by Aspergillus sp and inhaled as mold conidia, leading to hyphal growth and invasion of blood vessels, hemorrhagic necrosis, infarction, and potential dissemination to other sites in susceptible patients.

Symptoms and Signs: Noninvasive or, rarely, minimally locally invasive colonization of preexisting cavitary pulmonary lesions also may occur in the form of fungus ball (aspergilloma) formation or chronic progressive aspergillosis.

Primary superficial invasive aspergillosis is uncommon but may occur in burns, beneath occlusive dressings, after corneal trauma (keratitis), or in the sinuses, nose, or ear canal.

Invasive pulmonary aspergillosis usually extends rapidly, causing progressive, ultimately fatal respiratory failure unless treated promptly and aggressively. A. fumigatus is the most common causative species.

 Extrapulmonary disseminated aspergillosis may involve the liver, kidneys, brain, or other tissues and is usually fatal. Primary invasive aspergillosis may also begin as an invasive sinusitis, usually caused by A. flavus, presenting as fever with rhinitis and headache

Pathology gives explanations of a disease by studying the following four aspects of the disease.

1. Etiology,

2. Pathogenesis,

3. Morphologic changes and

4. Functional derangements and clinical significance.

1. Etiology Etiology of a disease means the cause of the disease. If the cause of a disease is known it is called primary etiology. If the cause of the disease is unknown it is called idiopathic. Knowledge or discovery of the primary cause remains the backbone on which a diagnosis can be made, a disease understood, & a treatment developed. There are two major classes of etiologic factors: genetic and acquired (infectious, nutritional, chemical, physical, etc).

2. Pathogenesis Pathogenesis means the mechanism through which the cause operates to produce the pathological and clinical manifestations. The pathogenetic mechanisms could take place in the latent or incubation period. Pathogenesis leads to morphologic changes.

3. Morphologic changes The morphologic changes refer to the structural alterations in cells or tissues that occur following the pathogenetic mechanisms. The structural changes in the organ can be seen with the naked eye or they may only be seen under the microscope. Those changes that can be seen with the naked eye are called gross morphologic changes & those that are seen under the microscope are called microscopic changes. the morphologic changes will lead to functional alteration & to the clinical signs & symptoms of the disease.

4. Functional derangements and clinical significance The morphologic changes in the organ influence the normal function of the organ. By doing so, they determine the clinical features (symptoms and signs), course, and prognosis of the disease.

HAEMORRHAGIC DISORDERS

Normal homeostasis depends on

 -Capillary integrity and tissue support.

- Platelets; number and function

(a) For integrity of capillary endothelium and platelet plug by adhesion and aggregation

(b) Vasoactive substances for vasoconstriction

(c) Platelet factor for coagulation.

(d) clot retraction.

- Fibrinolytic system(mainly Plasmin) : which keeps the coagulation system in check.

Coagulation disorders

These may be factors :

Deficiency .of factors

• Genetic.
• Vitamin K deficiency.
• Liver disease.
• Secondary to disseminated intravascular coagulation.or defibrinatian

Overactive fibrinolytic system.

Inhibitors of  the factors (immune, acquired).

Anticoagulant therapy as in myocardial infarction.

Haemophilia. Genetic disease transmitted as X linked recessive trait. Common in Europe. Defect in fcatorVII   Haemophilia A .or in fact .or IX-Haemaphilia B (rarer).

Features:

• May manifest in infancy or later.
• Severity depends  on degree of deficiency.
• Persistant wound bleeding.
• Easy Bruising with Hematoma formation

Nose bleed , arthrosis, abdominal pain with fever and leukocytosis

Prognosis is good with prevention of trauma and-transfusion of Fresh blood or fTesh plasma except for danger of developing immune inhibitors.

Von Willebrand's disease. Capillary fragility and decreased factor VIII (due to deficient stimulatory factor). It is transmitted in an autosomal dominant manner both. Sexes affected equally

Vitamin K  Deficiency. Vitamin K is needed for synthesis of factor II,VII,IX and X.

Deficiency maybe due to:

Obstructive jaundice.

Steatorrhoea.

Gut sterilisation by antibiotics.

Liver disease results in :

Deficient synthesis of factor I II, V, Vll, IX and X  Incseased fibrinolysis (as liver is the site of detoxification of activators ).

Defibrination syndrome. occurs when factors are depleted due to disseminated .intravascular coagulation (DIC). It is initiated by endothelial damage or tissue factor entering the circulation.

Causes

Obstetric accidents, especially amniotic fluid embolism. Septicaemia. .

Hypersensitivity reactions.

Disseminated malignancy.

Snake bite.

Vascular defects : (Non thrombocytopenic purpura).

Acquired :

Simple purpura a seen in women. It is probably endocrinal

Senile parpura in old people due to reduced tissue support to vessels

Allergic or toxic damage to endothelium due to  Infections like Typhoid Septicemia

Col!agen diseases.

Scurvy

Uraemia damage to  endothelium (platelet defects).

Drugs like aspirin. tranquillisers, Streptomvcin pencillin etc.

Henoc schonlien purpura Widespeard vasculitis due to hypersensitivity to bacteria or foodstuff

It manifests as :

Pulrpurric rashes.

Arthralgia.

Abdominal pain.

Nephritis and haematuria.

Hereditary :

(a) Haemhoragic telangieclasia. Spider like tortous vessels which bleed easily. There are disseminated lesions in skin, mucosa and viscera.

(b) Hereditary capillary fragilily similar to the vascular component of von Willbrand’s disease

.(c) Ehler Danlos Syndrome which is a connective tissue defect with skin, vascular and joint manifestations.

Platelet defects

These may be :

(I) Qualitative thromboasthenia and thrombocytopathy.

(2) Thrombocytopenia :Reduction in number.

(a) Primary or idiopathic thrombocytopenic purpura.

(b) Secondary to :

(i) Drugs especially sedormid

(ii) Leukaemias

(iii) Aplastic-anaemia.

Idiopathic thrombocytopenic purpura (ITP). Commoner in young females.

Manifests as :

Acute self limiting type.

Chronic recurring type.

Features:

(i) Spontaneous bleeding and easy bruisability

(ii)Skin (petechiae), mucus membrane (epistaxis) lesions and sometimes visceral lesions involving any organ.

Thrombocytopenia with abnormal forms of platelets.

Marrow shows increased megakaryocytes with immature forms, vacuolation, and lack of platelet budding.

Pathogenesis:

hypersensitivity to infective agent in acute type.

Plasma thrombocytopenic factor ( Antibody in nature) in chronic type