Genetic / Multi system Flashcards
Cystic fibrosis is an inherited disorder of x that affects fluid secretion in x glands and in the epithelial lining of the x,x and x
Clinical presentation
abnormal transport of chloride and bicarbonate ions mediated by an anion channel encoded by the cystic fibrosis transmembrane conductance regulator (CFTR)
that affects fluid secretion in exocrine glands and in the epithelial lining of the respiratory, gastrointestinal, and reproductive tracts.
In many individuals this disorder leads to abnormally viscous secretions that obstruct organ passages, resulting in most of the clinical features of this disorder, such as chronic lung disease secondary to recurrent infections, pancreatic insufficiency, steatorrhea, malnutrition, hepatic cirrhosis, intestinal obstruction, and male infertility. These manifestations may appear at any point in life from before birth to much later in childhood or even in adolescence.
Although cystic fibrosis follows an autosomal recessive transmission pattern, recent data suggest that even heterozygote carriers have a higher incidence of respiratory and pancreatic disease compared with the general population.
The primary defect in cystic fibrosis is abnormal transport of …
chloride and bicarbonate ions mediated by an anion channel encoded by the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7q31.2
The many clinical manifestations of mutations in the cystic fibrosis gene, from most severe to asymptomatic.
Pancreatic abnormalities are present in approximately x% of patients with cystic fibrosis.
85% to 90%
Exocrine pancreatic insufficiency occurs in the majority (85% to 90%) of patients with cystic fibrosis and is associated with “severe” CFTR mutations on both alleles (e.g., ΔF508/ΔF508), whereas 10% to 15% of patients with one “severe” and one “mild” CFTR mutation (e.g., ΔF508/R117H)
In milder cases, there may be only accumulation of mucus in the small ducts with some dilation of the exocrine glands. In more severe cases, usually seen in older children or adolescents, the ducts are completely plugged, causing atrophy of the exocrine glands and progressive fibrosis
CF. Over time, focal biliary cirrhosis develops in approximately x
Endocrine pancreatic insufficiency (i.e., diabetes mellitus) occurs in up to x% of adults with cystic fibrosis and is thought to be caused by severe destruction of pancreatic parenchyma including the islets.
one-third of patients
50%
Azoospermia and infertility are found in x% of males who survive to adulthood; congenital bilateral absence of the vas deferens is a frequent finding in these patients.
In some males, bilateral absence of the vas deferens may be the only feature suggesting an underlying CFTR mutation.
95%
Most common cause of death (~80%) in cystic fibrosis?
Cardiorespiratory complications, such as persistent lung infections, obstructive pulmonary disease, and cor pulmonale, are the
Clinical Features and Diagnostic Criteria for Cystic Fibrosis
Melanoma is the most deadly of all skin cancers and is strongly linked to acquired mutations caused by x (exposure to ?)
exposure to UV radiation in sunlight.
The great preponderance of melanoma arises in the skin; other sites of origin include the x
oral and anogenital mucosal surfaces (i.e., oropharynx, gastrointestinal and genitourinary tracts), the esophagus, the meninges, and the uvea of the eye
In about x% of affected patients, the risk of melanoma is inherited as an autosomal dominant trait with variable penetrance.
10% to 15%
Once a melanoma is excised, a number of pathologic features are used to gauge the probability of metastatic spread and prognosis. One model used to predict outcome is based in part on the following pathologic variables:
(1) tumor depth of invasion(Breslow thickness), (2) number of mitoses, (3) evidence of tumor regression (presumably due to the host immune response), (4) ulceration of overlying skin, (5) presence and number of tumor-infiltrating lymphocytes, and (6) location (central body or extremity).
The most important cause of cutaneous squamous cell carcinoma is DNA damage induced by exposure to UV light. Tumor incidence is proportional to the degree of lifetime sun exposure. A second common association is with x
immunosuppression
The term neuroblastic tumor includes tumors of the sympathetic ganglia and adrenal medulla that are derived from primordial neural crest cells populating these sites.
Neuroblastoma is the most important member of this family. It is the (how common) extracranial solid tumor of childhood, and the x diagnosed infant malignancy.
The median age at diagnosis is x months; approximately 40% of cases are diagnosed in infancy.
most common
most frequently
18
In childhood, about x% of neuroblastomas arise in the adrenal medulla.
40%
The remainder occur anywhere along the sympathetic chain, with the most common locations being the paravertebral region of the abdomen (25%) and posterior mediastinum (15%). Tumors may arise in numerous other sites, including the pelvis, the neck, and within the brain (cerebral neuroblastomas).
Neuroblastomas
Metastases, when they develop, appear x
In addition to local infiltration and lymph node spread, there is a pronounced tendency to spread through the bloodstream to the …
early and widely.
In addition to local infiltration and lymph node spread, there is a pronounced tendency to spread through the bloodstream to the liver, lungs, bone marrow, and bones
Prognostic Factors in Neuroblastomas
International Neuroblastoma Staging System
MEN-1, or Wermer syndrome, is a rare heritable disorder with a prevalence of about 2 per 100,000.
MEN-1 is characterized by abnormalities involving the
Parathyroid: Primary hyperparathyroidism is the most common manifestation of MEN-1 (80% to 95% of patients) and is the initial manifestation of the disorder in most patients, appearing in almost all patients by 40 to 50 years of age. Parathyroid abnormalities include both hyperplasia and adenomas.
Pancreas: Endocrine tumors of the pancreas are a leading cause of morbidity and mortality in persons with MEN-1. These tumors are usually aggressive and often present with metastatic disease. It is not uncommon to find multiple “microadenomas” scattered throughout the pancreas in conjunction with one or two dominant lesions. **gastrinomas and insulinomas most common
Pituitary: The most frequent anterior pituitary tumor encountered in MEN-1 is a prolactinoma; some patients develop acromegaly from somatotropin-secreting tumors.
In addition, carcinoid tumors, thyroid and adrenocortical adenomas, and lipomas are more frequent than in the general population.
MEN-1 syndrome is caused by germline mutations in the MEN1 tumor suppressor gene, which encodes a protein called x.
menin
MEN-2 is subclassified into three distinct syndromes:
MEN-2A, MEN-2B, and MEN-4.
MEN-2A, or Sipple syndrome, is characterized by:
phaeochromocytoma, medullary carcinoma of the thyroid, and parathyroid hyperplasia
MEN-2A is clinically and genetically distinct from MEN-1 and is caused by germline gain-of-function mutations in the x
RET protooncogene.
MEN-2B
Patients develop medullary thyroid carcinomas, which are usually multifocal and more aggressive than in MEN-2A, and pheochromocytomas.
Neuromas or ganglioneuromas involving the skin, oral mucosa, eyes, respiratory tract, and gastrointestinal tract, and a marfanoid habitus, with long axial skeletal features and hyperextensible joints
x is mutated in the germline of individuals with Li-Fraumeni syndrome, who have a greatly increased incidence of osteosarcoma.
TP53
BRCA1 and 2 associated cancers
and others
NF1
This is a common autosomal dominant disorder with a frequency of 1 in x.
It is a systemic disease associated with nonneoplastic manifestations and with a variety of tumors, including x.
3000
neurofibromas of all types, MPNSTs, gliomas of the optic nerve, other glial tumors and hamartomatous lesions, and pheochromocytomas
Other features include intellectual disability or seizures, skeletal defects, pigmented nodules of the iris (Lisch nodules), and cutaneous hyperpigmented macules (café au lait spots)
This is an autosomal dominant disorder resulting in a range of tumors, most commonly x
This disorder is much less common than NF1, having a frequency of 1 in x
This is an autosomal dominant disorder resulting in a range of tumors, most commonly bilateral eighth nerve schwannomas, multiple meningiomas, and ependymomas of the spinal cord. Many individuals with NF2 also have nonneoplastic lesions, which include nodular ingrowth of Schwann cells into the spinal cord (schwannosis), meningioangiomatosis (a proliferation of meningeal cells and blood vessels that grows into the brain), and glial hamartia (microscopic nodular collections of glial cells at abnormal locations, often in the superficial and deep layers of cerebral cortex).
This disorder is much less common than NF1, having a frequency of 1 in 40,000 to 50,000.
40,000 to 50,000.
Port wine stain in the distribution of the trigeminal nerve can be associated with x syndrome
Sturge-Weber syndrome
Marfan Approximately x% of cases are familial and transmitted by autosomal dominant inheritance. The remainder are sporadic and arise from new mutations.
70% to 85
Marfan phenotype
Skeletal abnormalities are the most striking feature of Marfan syndrome. Typically the patient is unusually tall with exceptionally long extremities and long, tapering fingers and toes. The joint ligaments in the hands and feet are lax, suggesting that the patient is double-jointed; typically the thumb can be hyperextended back to the wrist.The head is commonly dolichocephalic (long-headed) with bossing of the frontal eminences and prominent supraorbital ridges. A variety of spinal deformities may appear, including kyphosis, scoliosis, or rotation or slipping of the dorsal or lumbar vertebrae. The chest is classically deformed, presenting either pectus excavatum (deeply depressed sternum) or a pigeon-breast deformity.
Ocular changes take many forms. Most characteristic is bilateral subluxation or dislocation (usually outward and upward) of the lens, referred to as ectopia lentis. This abnormality, resulting from weakening of ciliary zonules, is so uncommon in persons who do not have this disease that the finding of bilateral ectopia lentis should raise the suspicion of Marfan syndrome.
Cardiovascular lesions are the most life-threatening features of this disorder. The two most common lesions are mitral valve prolapse, which occurs in 40% to 50% of cases and, of greater importance, dilation of the ascending aorta due to cystic medionecrosis. Histologically the changes in the media are virtually identical to those found in cystic medionecrosis not related to Marfan syndrome. Loss of medial support results in progressive dilation of the aortic valve ring and the root of the aorta, giving rise to severe aortic incompetence. Weakening of the media predisposes to an intimal tear, which may initiate an intramural hematoma that cleaves the layers of the media to produce aortic dissection. After cleaving the aortic layers for considerable distances, sometimes back to the root of the aorta or down to the iliac arteries, the hemorrhage often ruptures through the aortic wall.
Connective tissue disorder
As might be expected, tissues rich in collagen, such as skin, ligaments, and joints, are frequently involved in most variants of x
Ehlers-Danlos Syndromes (EDSs)
Rheumatoid arthritis (RA) is a x
Chronic autoimmune disorder that principally attacks the joints, producing a nonsuppurative proliferative and inflammatory synovitis
The autoimmune response in RA is initiated by CD4+ helper T cells.
Anti-citrullinated peptide antibodies (ACPAs) are diagnostic markers that can be detected in serum of up to x% of RA patients
70
It is estimated that 50% of the risk of developing RA is related to inherited genetic susceptibility.
RA typically affects small joints of the hands and feet. The characteristic histologic features include:
(1) synovial cell hyperplasia and proliferation;
(2) dense inflammatory infiltrates (frequently forming lymphoid follicles) of CD4+ helper T cells, B cells, plasma cells, dendritic cells, and macrophages
(3) increased vascularity due to angiogenesis
(4) fibrinopurulent exudate on the synovial and joint surfaces; and
(5) osteoclastic activity in subchondral bone, allowing the inflamed synovium to penetrate the bone and cause periarticular erosions and subchondral cysts.
Together, these changes produce the pannus, a mass of edematous synovium, inflammatory cells, granulation tissue, and fibroblasts that grows over and causes erosion of articular cartilage. In time, after the cartilage has been destroyed, the pannus bridges the apposing bones to form a fibrous ankylosis, which eventually ossifies and results in bone fusion, or bony ankylosis.
SLE is …
an autoimmune disease involving multiple organs, characterized by a vast array of autoantibodies, particularly antinuclear antibodies (ANAs), in which injury is caused mainly by deposition of immune complexes and binding of antibodies to various cells and tissues.
The hallmark of SLE is the production of autoantibodies, several of which (x) are virtually diagnostic.
antibodies to double-stranded DNA and the so-called Smith [Sm] antigen
SLE demographics
SLE predominantly affects women, with a frequency of 1 in 700 among women of childbearing age and a female-to-male ratio of 9 : 1 in the reproductive age group of 17 to 55 years.
Criteria for Classification of Systemic Lupus Erythematosus
Autoantibodies in Systemic Autoimmune Diseases
About 5% of Sjögren patients develop x, an incidence that is 40-fold greater than normal.
lymphoma
Certain other autoimmune disorders (e.g., Hashimoto thyroiditis) are also associated with a high risk of marginal zone lymphoma
x is characterized by: (1) chronic inflammation thought to be the result of autoimmunity, (2) widespread damage to small blood vessels, and (3) progressive interstitial and perivascular fibrosis in the skin and multiple organs.
Systemic sclerosis
Five groups of adults at high risk for developing AIDS
Men who have sex with men account for more than 50% of the reported cases
Heterosexual transmission, chiefly due to contact with members of other high-risk groups (e.g., intravenous drug users)
Intravenous drug users with no previous history of h sexuality are the next largest group, representing about 20% of infected individuals.
HIV infection of the newborn. Children of HIV-positive women are at risk for infection in utero, at birth, or through breast milk
Patients with hemophilia, especially those who received large amounts of factor VIII or factor IX concentrates before 1985, make up about 0.5% of all cases.
Recipients of blood and blood components who are not hemophiliacs but who received transfusions of HIV-infected whole blood or components (e.g., platelets, plasma) account for about 1% of patients. (Organs obtained from HIV-infected donors can also transmit the virus.)
AIDS-Defining Opportunistic Infections and Neoplasms Found in Patients With HIV Infection
The anatomic changes in the tissues are neither specific nor diagnostic. Common pathologic features of AIDS include …
opportunistic infections, KS, and B-cell lymphomas
Amyloidosis is a disorder characterized by…
the extracellular deposits of misfolded proteins that aggregate to form insoluble fibrils.
Hemophilia A is inherited as x trait
an X-linked recessive and thus affects mainly males and homozygous females
About 30% of patients have no family history; their disease is caused by new mutations.
Comparative Features of Type 1 and Type 2 Diabetes
Comparative Features of Type 1 and Type 2 Diabetes
Glucose homeostasis is tightly regulated by three interrelated processes:
glucose production in the liver; glucose uptake and utilization by peripheral tissues, chiefly skeletal muscle; and actions of insulin and counter-regulatory hormones, including glucagon, on glucose uptake and metabolism.
The most important class of hormones responsible for promoting insulin secretion from pancreatic β cells following feeding is the
incretins
The two most important incretins are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), both secreted by cells in the intestines following oral food intake.
The most important locus is the x, which according to some estimates contributes as much as 50% of the genetic susceptibility for T1D.
HLA gene cluster
90-95% of caucasions have this compared to normal
Long-term complications of diabetes
Clinical and Genetic Classification of Thalassemia
Differences Between Hodgkin and Non-Hodgkin Lymphomas
