autosomal dominant disorders

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ANASTACIO, Avelino Jr., Ledda BMLS IV GENERAL PATHOLOGY M 10:00 – 12:00 PM August 24, 2015 AUTOSOMAL DOMINANT DISORDERS Disease: Neurofibromatosis I (Von Recklinghausen Disease) Gene Defect: Microdeletion at 17q11.2 involving the NF1 gene Inheritance: Autosomal Dominant Clinical Features: The disorder is characterized by numerous benign tumors (neurofibromas) of the peripheral nervous system, but a minority of patients also show increased incidence of malignancy (neurofibrosarcoma, astrocytoma, Schwann cell cancers and childhood C). Multiple neurofibromas (Café au Lait spots) which may become malignant, Lisch nodules (pigmented hamartomas of the iris). Increased risk for tumors: pheochromocytoma, Wilms tumor, Rhabdomyosarcoma, leukemias.

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Page 1: Autosomal Dominant Disorders

ANASTACIO, Avelino Jr., Ledda BMLS IVGENERAL PATHOLOGY M 10:00 – 12:00 PM August 24, 2015

AUTOSOMAL DOMINANT DISORDERS

Disease: Neurofibromatosis I (Von Recklinghausen Disease)Gene Defect: Microdeletion at 17q11.2 involving the NF1 geneInheritance: Autosomal DominantClinical Features: The disorder is characterized by numerous benign tumors (neurofibromas) of the peripheral nervous system, but a minority of patients also show increased incidence of malignancy (neurofibrosarcoma, astrocytoma, Schwann cell cancers and childhood C).Multiple neurofibromas (Café au Lait spots) which may become malignant, Lisch nodules (pigmented hamartomas of the iris). Increased risk for tumors: pheochromocytoma, Wilms tumor, Rhabdomyosarcoma, leukemias.

Page 2: Autosomal Dominant Disorders

Disease: Tuberous SclerosisGene Defect:Mutations in the TSC1 or TSC2 geneInheritance: Autosomal DominantClinical Features: Tubers (glial nodules), seizures, mental retardation. Associated with adenoma sebaceum (facial lesion), myocardial rhabdomyomas, renal angiomyolipomas.

Disease: Hereditary SpherocytosisGene Defect:Nonsense and frameshift mutations of Ankyrin, Band 3, and SpectrinInheritance: Band-3 deficiency in RBC membrane - spherical shape to cells. Other RBC structural enzyme deficiencies can cause it, tooClinical Features: Sequestration of spherocytes in spleen - hemolytic anemia.

Disease:

Page 3: Autosomal Dominant Disorders

Marfan's SyndromeGene Defect: Fibrillin-1 gene (FBN1) encodes a microfibril-forming connective tissue proteinInheritance: Autosomal Dominant caused by mutations in the fibrillin gene on chromosome 15. Fibrillin Deficiency - faulty scaffolding in connective tissue (elastin has no anchor).Clinical Features: Arachnodactyly, dissecting aortic aneurysms, ectopia lentis (subluxation of lens), mitral valve prolapse.

Disease: Ehlers-Danlos SyndromeGene Defect: Defect in collagen and connective-tissue synthesis and structure.Inheritance: Various defects in collagen synthesis.

Type-I: Autosomal dominant, mildest form. Type-IV: Autosomal dominant. Defect in reticular collagen (type-III) Type-VI: Autosomal-recessive. Type-VII: Defect in collagen type I Type-IX: X-linked recessive

Clinical Features: Laxity of joints, hyperextensibility of skin, poor wound healing, aneurysms.

Type-I: Diaphragmatic hernia. Common, normal life-expectancy. Type-IV: Ecchymoses, arterial rupture. Dangerous due to rupture

aneurysms. Type-VI: Retinal detachment, corneal rupture

Disease: Osteogenesis Imperfecta

Page 4: Autosomal Dominant Disorders

Gene Defect: Defects in Collagen Type I formationInheritance: Autosomal Dominant DisorderConnective Tissue DiseaseClinical Features: Multiple fractures after birth, blue sclerae, thin skin, progressive deafness in some types (due to abnormal middle ear ossicles). The disorders are associated with deformed, undermineralized bones that are subject to frequent fracture.

Type-I is most common Type-II is most severe Type-IV is mildest form

Disease: Achondroplasia Gene Defect: Fibroblast growth factor receptor 3 (FGR3) – constitutively active (gain of function)Inheritance: Autosomal dominant (normal parents can have an affected child due to new mutation, and risk of recurrence in subsequent children is low) Clinical Features: Short limbs relative to trunk, prominent forehead, low nasal root, redundant skin folds on arms and legs.

Disease: Huntington Disease (Huntington Chorea)

Page 5: Autosomal Dominant Disorders

Gene Defect: Huntington (HD) – CAG repeat expansion within exon 1 (expansion occurs in father)Inheritance: Autosomal Dominant (gain-of function mutation)Shows anticipationClinical Features: Disorder is characterized by progressive motor, cognitive and psychiatric abnormalities. Chorea – nonrepetitive involuntary jerks – is observed in 90% of patientsProgressive dementia with onset in adulthood, choreiform movements, athetosis.

Disease: Myotonic Dystrophy Gene Defect: A protein kinase gene (DMPK) – CTG repeat expansion in 3’ untranslated region of the gene)Inheritance: Autosomal DominantShows anticipation Clinical Features: Disorder shows anticipation. Muscle weakness, cardiac arrhythmias, cataracts and testicular atrophy in males. Children born with congenital form have a characteristic open triangle-shaped mouth.

Disease: Polycystic Kidney Disease

Page 6: Autosomal Dominant Disorders

Gene Defect: Mutations in either polycystin-1 (PKD1) or polycystin-2 (PKD2) gene Inheritance: Autosomal Dominant (disease appears to follow a “two-hit model”, requiring the loss of both alleles of PDK1 or PDK2 for the disease to be evident. Clinical Features: Heterozygous individuals are predisposed to polycystic kidney disease because they are likely to lose the second good copy of the gene during their lifetime. Multiple renal cysts, blood in urine, end-stage renal disease and kidney failure.

Disease: Familial Polyposis ColiGene Defect: Germline mutation in the adenomatous polyposis coli (APC) gene.Inheritance: Inherited in an autosomal dominant manner. Approximately 75%-80% of individuals with APC-associated polyposis conditions have an affected parent. Offspring of an affected individual are at a 50% risk of inheriting the disease-causing mutation"Clinical Features: Patients with this condition gradually develop hundreds to thousands of colorectal polyps - small abnormalities at the surface of the intestinal tract, especially in the large intestine including the colon or rectum. These may bleed, leading to blood in the stool. 

Micrograph of atubular adenoma,the colorectal cancer precursor most commonly associated with FAP

Disease: Von Willebrand Disease

Page 7: Autosomal Dominant Disorders

Gene Defect: Von Willeband Factor DefectInheritance: Autosomal dominant and recessive varieties. Clinical Features: Hemorrhage, similar to hemophilia.

Type-I: Most mild Type-II: Intermediate Type-III: most severe, with recessive inheritance (complete absence)

Disease: Familial HypercholesterolemiaGene Defect: LDL-Receptor DefectInheritance: Autosomal Dominant (Haploinsufficiency)Clinical Features: Impaired uptake of LDL, elevated levels of LDL cholesterol, cardiovascular disease and stroke. Symptoms more severe in homozygous individuals.

Disease: Acute Intermittent PorphyriaGene Defect:

Page 8: Autosomal Dominant Disorders

Porphobilinogen Deaminase (PBGD) DeficiencyInheritance: Autosomal DominantClinical Features: Metabolic disorder affecting the production of heme, the oxygen-binding prosthetic group of hemoglobin. Acute porphyrias affect the nervous system and cause acute attacks of pain in the abdomen, limbs and elsewhere, nausea and vomiting, constipation, urinary retention, confusion, hallucinations, and seizures. Most cutaneous porphyrias cause chronic blistering and scarring on sun-exposed areas of the skin. One type causes an acute form of non-blistering photosensitivity. Porphyrias are also classified as either hepatic, meaning that the excess intermediates arise largely in the liver, or erythropoietic, in which they originate in the bone marrow.

Disease: Color BlindnessGene Defect: Mutations in the OPN1LW, OPN1MW, and OPN1SW genesInheritance: Autosomal DominantClinical Features: Color blindness are often observed by parents when children are young. In other cases, symptoms are so slight, they may not even be noticed. Common symptoms of color blindness include

Difficulty distinguishing between colors Inability to see shades or tones of the same color Rapid eye movement (in rare cases)