Section 16: Genetic Diseases

PSEUDOXANTHOMA ELASTICUM ICD-10: Q82.810

• Pseudoxanthoma elasticum (PXE) is a serious hereditary disorder of connective tissue that involves the elastic tissue in the skin, blood vessels, and eyes. Autosomal recessive (most common) and autosomal dominant. Incidence: 1:40,000 to 1:100,000.

• Etiology and Pathogenesis: Pathogenic mutation in the ABCC6 gene, which encodes MRP6, a member of the ATPase-dependent transmembrane transporter family of proteins. MRP6 can serve as an efflux pump transporting small-molecular-weight glutathione conjugates, which may facilitate calcification of elastic fibers. MRP6 is also thought to play a role in cellular detoxification.

• The principal skin manifestations are a distinctive peau d’orange surface pattern resulting from closely grouped clusters of yellow papules (cobblestoning) in a reticular pattern on the neck, axillae, and other body folds (Fig. 16-1).

• The effects on the vascular system include GI hemorrhage, hypertension occurring in young persons and resulting from involvement of renal arteries and claudication.

• Ocular manifestations (“angioid” streaks and retinal hemorrhages) can lead to blindness.

• Dermatopathology: Biopsy of a scar can detect characteristic changes of PXE before typical skin changes are apparent. Swelling and irregular clumping and basophilic staining of elastic fibers, which appear curled and “chopped up,” with calcium deposition.

• The course is inexorably progressive. Gastric artery hemorrhage → hematemesis. Peripheral vascular disease → cerebrovascular accidents, atherosclerosis obliterans, or bowel angina. Pregnancies are complicated by miscarriage and cardiovascular complications. Blindness. Life span is often shortened resulting from myocardial infarction or massive GI hemorrhage.

• Management: Genetic counseling. Evaluate family members for PXE. Regular re-evaluation by primary care physician and ophthalmologist is mandatory.

• Support organization: PXE International, www.pxe.org

TUBEROUS SCLEROSIS (TS) ICD-10: Q85.1

• Tuberous sclerosis is an autosomal-dominant disease arising from a genetically programmed hyperplasia of ectodermal and mesodermal cells and manifested by a variety of lesions in the skin, CNS (hamartomas), heart, kidney, and other organs.

• The principal early manifestations are the triad of seizures, mental retardation, and congenital white spots.

• Facial angiofibromata are pathognomonic but do not appear until the 3rd or 4th year.

EPIDEMIOLOGY

INCIDENCE In mental institutions, 1:100 to 1:300; in general population, 1:20,000 to 1:100,000.

AGE OF ONSET Infancy.

SEX Equal incidence.

RACE All races.

HEREDITY Autosomal dominant. TS is caused by mutations in a tumor-suppressor gene, either TSCS1 or TSCS2. TSCS1 maps to chromosome 9q34. TSCS2 maps to 16p13.3.

CLINICAL MANIFESTATION

White macules are present at birth or appear in infancy (>80% occur by 1 year of age, 100% appear ...