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Genetic & Developmental Disorders Slide list:
Slide Descriptions Slide 7-01. Skin, epidermolysis bullosa Epidermolysis bullosa is characterized by blister formation in response to mechanical trauma. This 3 year old had blistering over 60% of her body. Note the separation of the epidermis from the dermis at the dermal-epidermal junction. A careful examination of the cleavage plane shows accumulation of fluid and necrotic material, indicating that the cleavage occurred in vivo and is not an artifact of slide preparation. Mutations in genes coding for laminin 5 subunits (a3 chain, laminin b3 chain (this is the most commonly observed mutation), laminin g2 chain, collagen XVII, a6 integrin, and b4 integrin have been demonstrated to cause this form of epidermolysis bullosa.
Slide 7-02. Exocrine atrophy of the pancreas, cystic fibrosis At first glance, this tissue looks just like adipose tissue with scattered cellular foci that could be mistaken for inflammation. However, a closer look at these foci shows that the cells have too much cytoplasm to be lymphocytes and seem to have cellular connections that are not present between leukocytes. The tissue was obtained from the normal anatomic location of the pancreas and represents end-stage atrophy of the exocrine portion of the pancreas. This results from plugging of pancreatic ducts by the highly viscous secretions that are characteristic of cystic fibrosis and self-digestion via the pancreatic enzymes.
Slide 7-03. Lung, cystic fibrosis The greatly enlarged bronchi containing inspissated mucus are characteristic of the process of bronchiectasis and are readily visible on examination of the slide without magnification. Bronchial inflammation (acute and chronic bronchitis) and acute and chronic bronchopneumonia with scarring are also present.
Slide 7-04. Heterotopic pancreas, small bowel This lesion was discovered incidentally at autopsy, since it resulted in a grossly detectable nodule in the wall of the small bowel. Microscopic examination reveals tortuous duct profiles, lined by normal-appearing simple columnar epithelium. Ghosts of acini formed by pancreatic secretory epithelial cells can be seen in the bowel wall, with more viable cells present closer to the serosal surface. The presence of histologically normal tissue in an unusual place is called heterotopia. It represents a developmental defect rather than a neoplasm.
Slide 7-05. Thymus, severe combined immunodeficiency The thymus is small grossly. Microscopically, it consists of islands of thymic epithelial cells embedded in adipose tissue. Rather than the normal light lacy network of thymic epithelial cells that results from their multiple processes that enfold the developing thymocytes, these epithelial cells are in contact with each other. Some foci of epithelial cells exhibit a “pseudo-rosette” arrangement. Lymphocytes are almost totally absent. Hassall bodies form as the result of interactions between thymic epithelial cells and thymocytes, thus they are typically absent when thymopoiesis has not occurred.
Slide 7-06. Liver, Hurler’s syndrome The liver was grossly enlarged. Many hepatocytes appear pale and vacuolated due to accumulation of storage product. Hurler’s syndrome is due to a-L-iduronidase deficiency , which leads to faulty degradation of dermatan and heparan sulfate and storage of these undegraded glycosaminoglycans in organs and connective tissue. The storage product is highly water-soluble, but can be demonstrated using a colloidal iron stain.
Slide 7-07. Heart, sialic acid storage disease The cardiac myocytes are enlarged by vacuoles that appear empty due to loss of the highly water-soluble storage product during tissue processing. The disease results from a defect in the transporter that transports sialic acid out of lysosomes following degradation of proteins that contain this molecule. The disease is fatal during infancy due to organ dysfunction that results from the sialic acid-filled lysosomes.
Slide 7-08. Skeletal muscle and cartilage, centronuclear myopathy The striated muscle tissue on this slide clearly must be skeletal muscle, given its proximity to the cartilage (which was obtained from a rib). However, the muscle fibers are thin and poorly developed. Rather than having nuclei on the outside, between 25 and 50% of the fibers have nuclei present in their central portion. Centronuclear myopathy (also known as myotubular myopathy) is a congenital disorder with 3 subtypes based on the age of onset of clinical disease. The early or infantile form presents as a floppy infant at birth. The juvenile form is the most common and presents in late infancy with slowly progressive muscle weakness. The adult form has a relatively benign course. The infantile form of centronuclear myopathy shown here is rare, with only 15 families described in the literature by 1990 (Darnfors et al. Clin. Genetics 37:335-340, 1990). It has an X-linked recessive form of inheritance. Affected infants are severely hypotonic with respiratory distress. Prenatally, these infants exhibit polyhydramnios and weak fetal movements (Donders et al. Eur. J. Obstet. Gynecol. Reprod. Biol. 24:33-38, 1987). The neonatal mortality is 80%. The major histologic findings are muscle fibers with centrally placed nuclei in 10-50% of fibers, with perinuclear halos (Sasaki et al. Brain Develop. 11:26-32, 1989). All of these features were present in the current case. The gene for this disorder was localized by positional cloning to Xq28, corresponding to the myotubularin locus. Myotubularin has a tyrosine phosphatase (PTP) domain and is highly conserved through evolution. A variety of mutations were discovered in patients with X-linked centronuclear myopathy, including point mutations, deletions, and splice mutations. Five point mutations were found in multiple unrelated patients, accounting for 27% of the observed mutations. The possibility of detecting mutations and determining carrier status in a disease with a high proportion of sporadic cases is of importance for genetic counselling. More than half of these mutations are expected to inactivate the putative enzymatic activity of myotubularin, either by truncation or by missense mutations affecting the predicted PTP domain.
Slide 7-09. Liver, adult polycystic kidney disease The liver has focal steatosis. Other notable lesions are a proliferation of large often tortuous bile ducts, both on the surface of the liver and within the parenchyma. This lesions are called biliary microhamartomas or Von Meyenberg Complexes. The pathogenesis of these lesions is not well-understood, but they are commonly observed in patients with polycystic kidney disease, suggesting a defect shared between kidney tubular and biliary epithelial cells. The lung tissue that is also present on this slide shows poor aeration, but is otherwise normal.
Slide 7-10. Kidney, adult polycystic kidney disease Grossly, the kidney contained numerous large, fluid-filled cysts that disrupted the architecture and function of the kidney. The section here shows portions of 5 or 6 different cysts. The cyst lining has a simple squamous appearance. Although many of the tubules show signs of autolysis, the glomeruli are fairly well-preserved in this kidney. This patient was asymptomatic and his polycystic kidney disease was diagnosed at autopsy after death due to an unrelated illness.
Additional slides from the Duke Medical School Pathology Teaching Collection: CASE NUMBER 1 Clinical History: This 15-day-old female child had multiple congenital cardiac defects. In addition, bilateral abdominal masses were present. Microscopic: This is a complete hemisection of the kidney. Examination with naked eye or inverted ocular reveals that the entire kidney has a honeycombed appearance. Microscopic examination shows the cysts to be markedly dilated tubules that contain granular eosinophilic material (probably protein) and in some cases, red blood cells. The glomeruli, in contrast to those of an adult kidney, contain peripheral rows of visceral epithelial cells. This pattern, which disappears during the course of several years, is normal for infant glomeruli. Polycystic renal disease may also present in adulthood, in which case the kidneys are often grossly enlarged and virtually replaced by cysts up to several centimeters in diameter. DIAGNOSIS: Polycystic Kidney Image Gallery:
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