Autosomal Dominant Disorders

· XXX syndrome—this is trisomy XXX and other multiple X-chromosomal abnormalities. Many of these girls are phenotypically normal but may have mild mental retardation and menstrual abnormalities.

· DiGeorge syndrome—this is also known as 22q11.2 deletion syndrome and is a syndrome caused by the deletion of a small segment of chromosome 22. There is failure of the development of the third and fourth pharyngeal pouches so there is agenesis of the parathyroid glands and thymus. There is T-cell deficiency, hypocalcemia, congenital heart problems, certain facial features, frequent infections, developmental delay, learning problems and cleft palate.

AUTOSOMAL DOMINANT DISORDERS

Autosomal dominant disorders have the characteristic of being associated with an autosomal gene and not a sex gene. It is dominant, meaning there is no carrier state as the individual who has the disorder will likely have the disease unless there is incomplete penetrance. The likelihood of passing on this type of gene disorder is 50 percent to both male and female offspring. These are the major autosomal dominant disorders:

· Autosomal dominant polycystic kidney disease—this has an onset in adult life and can lead to chronic renal failure and death. There are multiple cysts in the kidneys, leading to enlarged kidneys. There may also be liver cysts. People with this condition are born with one mutated copy of the PKD1 or PKD2 gene in each cell. About 90 percent of these cases are inherited with the rest being sporadic mutations.

· Ehlers-Danlos syndrome—this represents a wide-ranging group of inherited, usually autosomal dominant disorders, involving different defects in collagen synthesis. This connective tissue disease involves joint laxity, extreme elasticity of the skin, and poor wound healing. The most common cause of death is a dissecting aortic aneurysm.

· Familial hypercholesterolemia—this is an autosomal dominant defect in the LDLreceptor. It leads to accelerated atherosclerosis in the person who is heterozygous

and, in the person who is homozygous, it leads to a high possibility of an MI by thirty-five years of age. Patients will have obvious xanthomas in the skin.

· Osler-Weber-Rendu Syndrome—this is also referred to as hereditary hemorrhagic telangiectasia syndrome. This is an autosomal dominant syndrome in which the person has multiple telangiectasias of the mucus membranes and skin. These patients will have nose bleeds but will have a normal life expectancy.

· Hereditary spherocytosis—this is an autosomal dominant disorder involving a defect in the RBC membrane, leading to a spherical shape to the red blood cells.

Patients will have hemolytic anemia from sequestration of spherocytes in the spleen and will have splenomegaly.

· Huntington disease—this is an autosomal dominant disease with 100 percent penetrance. There is a genetic defect of chromosome 4, leading to atrophy of the putamen, caudate nuclei, and frontal cortex. Progressive dementia results with athetosis, choreiform movements, and early onset dementia.

· Marfan syndrome—this is an autosomal dominant connective tissue disease.

There is a deficiency of the fibrillin protein so that the elastin protein has no anchor. These patients tend to be tall and thin. Patients can die from a dissecting aortic aneurysm and will have subluxation of the lens and mitral valve prolapse.

There will also be a risk of arachnodactyly (in which the fingers and toes are abnormally long and slender).

· Neurofibromatosis—this is also referred to as von Recklinghausen disease. It is an autosomal dominant disorder from a defect in the NF1 gene. This leads to multiple neurofibromas of the nerve tissue, with the possibility that these can become malignant, Lisch nodules (pigmented hamartomas of the iris), and caféau-Lait spots in the skin. There is an increased risk for other cancers or tumors, such as Wilms tumor, leukemias, and pheochromocytoma.

· Tuberous sclerosis—this is an autosomal dominant disorder caused by changes (mutations) in either the TSC1 or TSC2 gene. These genes are involved in regulating cell growth, leading to multiple glial nodules called tubers. Patients

will have mental retardation, facial lesions, angiomyolipomas, and myocardial rhabdomyomas.

· Von Hippel-Lindau syndrome—this is an autosomal dominant disorder that involves the short arm of chromosome 3, which is the same gene region associated with renal cancer. Besides a high risk for renal cancer, patient will have visceral cysts, adenomas, and hemangioblastomas of the brain or retina.

· Selective IgA deficiency—this can be either autosomal dominant or autosomal recessive. It involves deficiency of IgA from a failure of heavy-chain gene switching. It is the most common hereditary immune deficiency disease. There are diseases related to IgM and IgG deficiency but these are not as common.

· Job’s syndrome—this is an autosomal dominant hyper IgE syndrome that is secondary to the failure to make gamma-interferon by the helper T cells. This leads to an increase in TH2 cells and high IgE levels. The histamine levels will be high and there will be eosinophilia. Recurrent staphylococcus infections and eczema are seen in people who have this. There is a related disorder that is autosomal recessive.

· Chronic mucocutaneous candidiasis—this is autosomal dominant or autosomal recessive and leads to T-Cell deficiency specific to Candida. The individual with this disorder will have recurrent candida infections that require ongoing treatment with anti-fungal medications.

· Osteogenesis imperfecta—this is an autosomal dominant connective tissue disease that leads to defects in type 1 collagen formation. There will be a history of frequent fractures starting in infancy, thin skin, and progressive deafness in some patients. There are mild and severe cases.