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Chapter: Pathology: Genetic Disorders

Autosomal Dominant Disorders

Familial hypercholesterolemia is the most common inherited disorder (incidence1 in 500) and is due to a mutation in the low density lipoprotein (LDL) receptor gene (LDLR) on chromosome 19.


Familial hypercholesterolemia is the most common inherited disorder (incidence1 in 500) and is due to a mutation in the low density lipoprotein (LDL) receptor gene (LDLR) on chromosome 19. The mutations in the LDL receptor cause increased levels of circulating cholesterol, loss of feedback inhibition of HMG-coenzyme A (HMG-CoA) reductase, and increased phagocytosis of LDL by macrophages.

There are 5 major classes of mutation.

·            Class I: no LDL receptor synthesis


·            Class II: defect in transport out of the endoplasmic reticulum


·            Class III: defect in LDL receptor binding


·            Class IV: defect in ability to internalize bound LDL


·            Class V: defect in the recycling of the LDL receptor


Clinical features include elevated serum cholesterol (heterozygotes have elevations of 2–3 times the normal level and homozygotes have elevations of 5–6 times the normal level), skin xanthomas (collections of lipid-laden macrophages), xanthelasma around the eyes, and premature atherosclerosis (homozygotes often develop myocardial infarctions in late teens and twenties).

Marfan syndrome is due to a mutation of thefibrillingene (FBN1) on chromosome15q21. Fibrillin is a glycoprotein that functions as a scaffold for the alignment of elastic fibers.

Clinical features include skeletal changes (tall, thin build with long extremities, hyperextensible joints, pectus excavatum [inwardly depressed sternum], and pec-tus carinatum [pigeon breast]) and abnormal eyes (ectopia lentis, characterized by bilateral subluxation of the lens). The cardiovascular system is also particularly vulnerable; it may show cystic medial degeneration of the media of elastic arteries with a loss of elastic fibers and smooth muscle cells with increased risk of dissecting aortic aneurysm (a major cause of death), dilatation of the aortic ring potentially leading to aortic valve insufficiency, and/or mitral valve prolapse.

Ehlers-Danlos syndrome (EDS) is a group of inherited connective tissue diseases thathave in common a defect in collagen structure or synthesis. Clinically, the disease causes hyperextensible skin that is easily traumatized and hyperextensible joints sec-ondary to effects on the joints and adjacent ligaments.

There are a number of variants with different modes of inheritance.

·            Kyphoscoliotic EDS: autosomal recessive form


·            Vascular variant EDS: autosomal dominant form that causes rupture of ves-sels and bowel wall


·              Classical EDS: autosomal dominant form that causes a type V collagen defect;patients have a normal lifespan


Type 1 (von Recklinghausen disease) neurofibromatosis (90% of cases) has an inci-dence of 1 in 3,000. The condition is due to a mutation of the tumor suppressor gene NF1 located on chromosome 17 (17q11.2). The normal gene product (neurofibromin)inhibits p21 ras oncoprotein.

·              Affected individuals characteristically have multiple neurofibromas and benign tumors of peripheral nerves that are often numerous and may be disfiguring. The plexiform variant of the neurofibromas are diagnostic.


·              Rarely (3%), malignant transformation of a neurofibroma may occur.


·              Other clinical features include pigmented skin lesions (6 or more “cafe-au-lait spots” that are light brown macules usually located over nerves); pigmented iris hamartomas (Lisch nodules); and increased risk of meningiomas and pheo-chromocytoma, an adrenal tumor that also occurs with von Hippel-Lindau disease and MEN 2.

Type 2 (bilateral acoustic) neurofibromatosis (10% of cases) has an incidence of 1 in 45,000.

·              There is a mutated tumor suppressor gene NF-2 (22q12.2) on chromosome 22.


·              The normal gene product (merlin) is a critical regulator of contact-dependent inhibition of proliferation.


·              Clinical features include vestibular schwannomas (acoustic neuromas), and increased risk of meningioma and ependymomas.

von Hippel-Lindau disease is due to a mutation of the tumor suppressor geneVHLon chromosome 3p (3p26-p25). The normal gene product’s main action is to tag proteins (e.g., hypoxia inducible factor 1a [a transcription factor that induces the expression of angiogenesis factors]) with ubiquitin for degradation.

Clinical manifestations can include retinal hemangioblastoma (von Hippel tumor); hemangioblastomas of the cerebellum, brain stem, and spinal cord (Lindau tumor); cysts of the liver, pancreas, and kidneys; and multiple bilateral renal cell carcinomas.


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