Genetic homogeneity of autoimmune polyglandular disease type I

Autoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease (MIM 240300) characterized by hypoparathyroidism, primary adrenocortical failure, and chronic mucocutaneous candidiasis. The disease is highly prevalent in two isolated populations, the Finnish population and the Iranian Jewish one. Sporadic cases have been identified in many other countries, including almost all European countries. The APECED locus has previously been assigned to chromosome 21q22.3 by linkage analyses in 14 Finnish families. Locus heterogeneity is a highly relevant question in this disease affecting multiple tissues and with great phenotypic diversity. To solve this matter, we performed linkage and haplotype analyses on APECED families rising from different populations. Six microsatellite markers on the critical chromosomal region of 2.6 cM on 21q22.3 were analyzed. Pairwise linkage analyses revealed significant LOD scores for all these markers, maximum LOD score being 10.23. The obtained haplotype data and the geographic distribution of the great-grandparents of the Finnish APECED patients suggest the presence of one major, relatively old mutation responsible for approximately 90% of the Finnish cases. Similar evidence for one founder mutation was also found in analyses of Iranian Jewish APECED haplotypes. These haplotypes, however, differed totally from the Finnish ones. The linkage analyses in 21 non-Finnish APECED families originating from several European countries provided independent evidence for linkage to the same chromosomal region on 21q22.3 and revealed no evidence for locus heterogeneity. The haplotype analyses of APECED chromosomes suggest that in different populations APECED is due to a spectrum of mutations in a still unknown gene on chromosome 21.     

Salivary duct carcinoma: a clinicopathologic study of three cases with a review of the literature

Three cases of salivary duct carcinoma are presented. They occurred in a 60 year old man, a 66 year old man and a 57 year old woman. All of the lesions were located in the parotid gland. The tumor size ranged from 3 to 5 cm across the largest diameter. Facial paralysis was observed in two cases. Histologically, intraductal and invasive adenocarcinoma showing papillary, cribriform, and solid patterns with comedolike necrosis was observed. Immunohistochemically, the tumor cells were positive for keratin and epithelial membrane antigen. No myoepithelial cells were demonstrated within the tumor by staining for S-100 protein, alpha-smooth muscle actin or muscle specific actin. Ultrastructurally, intracytoplasmic lumina with microvilli, a moderate number of mitochrondria, lysosomes, and tight junctions were found. Regional lymph node metastasis was observed in one case, and distant metastasis developed in two cases. All of the patients were treated with adjuvant postoperative irradiation. One patient died of disease at 11 months after the initial diagnosis, another was alive with disease at 8 months, and the third patient was alive without disease at 2 years and 3 months. Salivary duct carcinoma should be differentiated from low-grade salivary gland carcinomas using morphologic and clinical criteria because of its poor prognosis even with aggressive therapy.     

Progressive multifocal leukoencephalopathy in AIDS: a clinicopathologic study and review of the literature

We reviewed the clinical, radiographic, and pathologic features of 15 patients with the acquired immune deficiency syndrome (AIDS) and progressive multifocal leukoencephalopathy (PML). Brain tissue from 10 autopsy and 6 biopsy specimens was studied using: in situ hybridization (ISH) for JC virus (JCV), immunohistochemistry for human immunodeficiency virus (HIV) p24 antigen, and electron microscopy. Thirteen patients presented with focal neurologic deficits, while 2 presented with a rapid decline in mental status. PML was commonly the initial opportunistic infection of AIDS and produced hemiparesis, dementia, dysarthria, cerebellar abnormalities, and seizures. Magnetic resonance imaging was more sensitive than computed tomography in detecting lesions, and often showed multifocal areas of PML. CD4+ T-cell counts were uniformly low (mean 84/mm3), except in 1 patient who improved on 3'-azido-3'-deoxythymidine (AZT). PML involved the cerebral hemispheres, brain stem, cerebellum, and cervical spinal cord. The distribution of brain involvement was consistent with hematogenous dissemination of the virus. In 2 brain specimens, multiple HIV-type giant cells were present within the regions involved by PML. When co-infection by HIV and papovavirus was present, PML dominated the pathological picture. ISH for JCV showed virus in the nuclei of oligodendrocytes and astrocytes. Occasionally there was staining for JCV in the cytoplasm of glial cells and in the neuropil, the latter possibly a correlate of papovavirus spread between myelin sheaths, as seen by electron microscopy. ISH demonstrated more extensive foci of PML than did routine light microscopy.     

Focal nodular hyperplasia of the liver: a clinicopathologic study and review of the literature

We received the clinical records and pathologic material of 20 patients with biopsy proven hepatic focal nodular hyperplasia. The majority of the patients were females of child bearing age, five of whom had a history of oral use of contraceptives. In every instance focal nodular hyperplasia was an incidental finding; liver function tests were always normal. Focal nodular hyperplasia is a distinct histopathologic entity, distinguishable from liver cell adenoma. Specifically it consists of nodular aggregates of cytologically normal hepatocytes with foci of intranodular bile duct proliferation. Focal nodular hyperplasia appears to be a benign entity, even in patients in whom the lesion was not excised. The association between focal nodular hyperplasia and oral use of contraceptives may be coincidental, although hormonally related vascular changes may be responsible for rupture of the lesion.     

Minocycline-related autoimmune hepatitis: case series and literature review

BACKGROUND: Minocycline is an antibiotic commonly used in the treatment of adolescent acne. OBJECTIVES: To describe the clinical, laboratory, and histological features in 3 cases of minocycline-related autoimmune hepatitis and to review the literature of similar cases in the adolescent population. DESIGN: Case series. SETTING: Patients were cared for in the Division of Gastroenterology, Children's Hospital, Boston, Mass. RESULTS: Three adolescents (age, 15-16 years), while being treated with therapeutic doses of minocycline for periods of 12 to 20 months, met the 1993 International Autoimmune Hepatitis Group criteria for autoimmune hepatitis. All had a positive antinuclear antibody titer. Other features included hypergammaglobulinemia and a positive anti-smooth muscle antibody titer. Two patients underwent liver biopsy that revealed severe chronic lymphoplasmacytic inflammation, necrosis, and fibrosis. All other causes of liver disease were excluded. One patient had resolution of symptoms with withdrawal of the drug, while 2 required immunosuppression therapy. A review of the literature yielded only 18 similar cases, none in the pediatric literature, the majority of which contained incomplete pertinent data. CONCLUSIONS: Minocycline is related to the development of autoimmune hepatitis in some adolescents. Pediatricians who use this drug for treatment of acne should be aware of this serious potential relation and stop the drug immediately when suspicion is raised.     

Ocular adnexal oncocytoma: a case series and clinicopathologic review of the literature

OBJECTIVE: Headache is a common complaint in children and brain imaging has become widely used to evaluate this clinical condition. We studied the value of neuroimaging in children with chronic headaches. PATIENTS AND METHODS: A retrospective chart review was conducted of all children referred to the pediatric outpatient clinic for evaluation of headache over a 3-year period. The charts were reviewed for headache characteristics, clinical indications for performing neuroimaging, and imaging results. Special attention was paid to evidence of space-occupying lesions. RESULTS: A total of 160 records were studied, with subjects ranging in age from 4 to 14 years. Most patients were diagnosed as having migraine headaches (60%) or chronic tension headaches (29.5%). Other diagnoses were post-traumatic (6%) and unclassified (4%). Sixty-six patients (41%) had computed tomography imaging performed. In most cases, brain imaging studies were performed because of clinical data (41%) like atypical pattern, sleep-related headache or increase of headache, because of the parents' concerns about brain lesions (38%) and because of an age less than 5 years (14%). Structural changes were found on brain imaging in 4 patients, but none indicated the presence of a treatable space-occupying lesion and all were deemed unrelated to the headache. Our findings of no relevant abnormalities in a series of 66 neuroimaging studies indicate that the maximal rate at which such abnormalities might appear in this population is 4.4%. CONCLUSIONS: These results indicate that neuroimaging studies have very limited value in the clinical evaluation of pediatric patients with chronic headache and should be reserved for those patients with clinical evidence suggestive of underlying structural lesion.     

Carcinoid disease: review of the literature

A novel method is described for assessing drug bioavailability from pharmacologic data. The method is based upon a generalized model for the relationship between the observed effect (E) and the input rate (f): E = phi (ce delta * f), where * denotes convolution, ce delta is effect site unit impulse response ("amount" of drug at the effect site resulting from the instantaneous input of a unit amount of drug) and phi is transduction function (relates "amount" of drug at the effect site to E). The functions phi and ce delta are expressed as cubic splines for maximum versatility. Pharmacologic data collected after the administration of two different doses by i.v. infusion are analyzed simultaneously to estimate the function parameters. This experimental design addresses the fact that phi and ce delta cannot be uniquely estimated from the results of a single dose experiment. The unknown f from a test treatment is then estimated by applying an implicit deconvolution method to the pharmacologic data collected during that treatment. The method was tested with stimulated data. The method and the model were further evaluated by application to a clinical study of verapamil (V) pharmacodynamics in 6 healthy volunteers. Simulations showed that the method is accurate and precise in the presence of a high degree of measurement error, but large intrasubject variability in the model functions can result in biased estimates of the amount absorbed. The method produced reasonably accurate estimates of the V input rate and systemic availability (F) in the 6 human volunteers though there was a trend towards underestimation (estimated total F% = 93.6 +/- 14 vs. the true F% of 100).     

Duodenal involvement of Crohn''s disease: three different clinicopathologic patterns

Autosomal dominant polycystic kidney disease (ADPKD) describes a group of at least three genetically distinct disorders with almost identical clinical features that collectively affects 1:1,000 of the population. Affected individuals typically develop large cystic kidneys and approximately one half develop end-stage renal disease by their seventh decade. It has been suggested that the diseases result from defects in interactive factors involved in a common pathway. The recent discovery of the genes for the two most common forms of ADPKD has provided an opportunity to test this hypothesis. We describe a previously unrecognized coiled-coil domain within the C terminus of the PKD1 gene product, polycystin, and demonstrate that it binds specifically to the C terminus of PKD2. Homotypic interactions involving the C terminus of each are also demonstrated. We show that naturally occurring pathogenic mutations of PKD1 and PKD2 disrupt their associations. We have characterized the structural basis of their heterotypic interactions by deletional and site-specific mutagenesis. Our data suggest that PKD1 and PKD2 associate physically in vivo and may be partners of a common signalling cascade involved in tubular morphogenesis.     

Thyroid paraganglioma: a clinicopathologic and immunohistochemical study of three cases

We report three cases of intrathyroidal paraganglioma. The patients were adult women without significant personal or family histories that presented with an asymptomatic thyroid nodule. The tumors were single, well-circumscribed solid masses, 2 cm in greatest diameter, located within one thyroid lobe. Microscopically, they were encapsulated and showed the typical nesting (Zellballen) pattern of paraganglioma in other sites. Two of the tumors were composed of small- to medium-sized cells with granular amphophilic cytoplasm, and the third consisted of relatively large cells having a similar staining quality. Immunohistochemically, all tumors showed positivity for neuron-specific enolase, chromogranin A, and synaptophysin. S-100 protein-positive sustentacular cells were demonstrated in each case. Negative staining for epithelial markers, thyroglobulin, carcinoembryonic antigen, calcitonin, calcitonin gene-related peptide, serotonin, vimentin, and Congo red excluded other tumors that were considered in the differential diagnosis, such as medullary carcinoma, hyalinizing trabecular adenoma, atypical follicular adenoma, Hurthle-cell neoplasm, and metastatic carcinoid tumor. The patients were alive and well without evidence of recurrent disease at the time of the last follow-up. The previous literature on these tumors is discussed. We conclude that intrathyroidal paraganglioma exists and that this tumor can be distinguished from other similar-appearing neoplasms in this organ.     

Giant colonic diverticulum: presentation of one case and review of the literature

Since the first case described in 1946, fewer than 100 cases of giant colonic diverticula have been reported in the literature. We discuss the clinical, radiologic, and pathologic findings in a case of giant colonic diverticulum and review the etiology and differential diagnosis.     

Leri's melorheostosis: three pediatric cases and a review of the literature

Three pediatric cases of melorheostosis are described. Growth disorders of the limbs are often the first signs in children. The radiological appearance consists of long tracks of increased cortical radiodensity in the long bones and of small dense islets in the epiphyses.     

Primary pulmonary rhabdomyosarcomas: a clinicopathologic and immunohistochemical study of three cases

Three cases of primary pulmonary rhabdomyosarcoma in adults are presented. The patients were all men between the ages of 57 and 78 yr (mean 67.5). All patients presented with symptoms referable to their tumors, including cough, shortness of breath, pleuritic chest pain, and weight loss. In one patient, a history of tobacco and alcohol abuse was obtained. Anatomically, two tumors were located in the left upper lobe and one in the left lower lobe. Grossly, the tumors ranged in size from 6 to 11.5 cm and were tan-gray, firm masses with areas of necrosis and hemorrhage. Histologically, the tumors were characterized by a spindle cell proliferation admixed with areas showing a pleomorphic cell population with numerous rhabdomyoblasts and areas of hemorrhage and necrosis. Immunohistochemically, all three tumors showed strong positivity with desmin and myoglobin antibodies and negative staining with antibodies against keratin, epithelial membrane antigen, and S-100 protein. All patients had a fatal outcome. Two patients died a few days after admission with respiratory distress; the third one died 2 years after diagnosis with widely metastatic disease. Autopsy findings in all cases disclosed disseminated metastases to multiple abdominal and thoracic organs. Primary pulmonary rhabdomyosarcoma should be considered in the differential diagnosis of poorly differentiated pulmonary neoplasms in adults and should be distinguished from other primary and metastatic sarcomas.     

Liver transplantation: review of the literature. Part 3: Medical complications

The first attempted human orthotopic liver transplantation, in 1963, involved a child with biliary atresia, who died on the operating table as a result of uncontrollable coagulopathy. Improvements in immunosuppression, surgical technique, medical imaging and postoperative care, as well as more stringent patient selection, have allowed the development of liver transplantation and its universal acceptance as the treatment for a variety of liver diseases. The radiologist plays a major role in the multidisciplinary transplantation team and must be familiar with each stage of orthotopic liver transplantation and its associated complications. In the first article of this series (Can Assoc Radiol J 1997;48[3]: 171-178), the authors reviewed the anatomic features and current concepts relevant to orthotopic liver transplantation. In the second article (Can Assoc Radiol J 1997;48[4]: 231-242), they discussed the vascular and biliary complications of the operation. This, the third and final article in the series, covers the medical complications.     

Biliary dyskinesia: a study of more than 200 patients and review of the literature

The aim of this study was to establish, by means of peripheral quantitative computed tomography (pQCT) at the distal radius, the existence of cortical and/or trabecular osteopenia, and to assess the integrity of bone geometry in uremic patients undergoing maintenance hemodialysis. Our results show a clearcut selective reduction in volumetric cortical density, more evident in women (p = -0.0001) than men (p = 0.030), which appears to be independent of age and menopausal status. Trabecular density was not significantly changed in either sex. Cortical density of the patients correlated inversely with age (p = 0.003), duration of dialysis (p = 0.002) and parathyroid hormone (PTH) levels (p = 0.03). Trabecular density correlated only with age. Normally, cortical density is age-dependent and its reduction is accompanied by compensatory geometry changes. Compared with control subjects, in our female patients both cortical area and cortical thickness were reduced (p = 0.02 and 0.008), while cross-sectional area did not change (p = 0.67). Conversely, in the males only cross-sectional area was reduced (p = 0.02). In conclusion, in uremic patients we observed a selective cortical osteopenia, more evident in the female sex, and a sex-specific pattern of geometry impairment, with resultant apparent increased bone fragility in the uremic women. We suggest that the prolonged PTH excess could be responsible, directly and/or interacting with estrogen deficiency.     

Primary biliary cirrhosis associated with mixed type autoimmune hemolytic anemia and sicca syndrome: a case report and review of literature

A case presenting with an unusual association of primary biliary cirrhosis and mixed type autoimmune hemolytic anemia plus sicca syndrome is described. The 49-yr-old female primary biliary cirrhosis patient had a confirmed sicca syndrome and presented with jaundice and life-threatening anemia. Laboratory tests revealed positive Coombs' test with coexisting cold and warm autoantibodies. She was successfully treated by blood transfusion with packed red cells lacking any red cell antigens corresponding to serum alloantibodies and pulse methylprednisolone therapy. The patient remained stable under maintenance treatment using oral steroids and ursodeoxycholic acid. This case is probably the first reported showing an association between primary biliary cirrhosis and mixed type autoimmune hemolytic anemia plus sicca syndrome and was probably induced by heterogenous and complicated autoimmune reactions.     

Liver transplantation: review of the literature. Part 2: Vascular and biliary complications

The first attempted human orthotopic liver transplantation, in 1963, involved a child with biliary atresia, who died on the operating table as a result of uncontrollable coagulopathy. Improvements in immunosuppression, surgical technique, medical imaging and postoperative care, as well as more stringent patient selection, have allowed the development of liver transplantation and its universal acceptance as the treatment for a variety of liver diseases. The radiologist plays a major role in the multidisciplinary transplantation team and must be familiar with each stage of orthotopic liver transplantation and its associated complications. In the first article of this series (Can Assoc Radiol J 1997;48[3]:171-178), the authors reviewed the anatomic features and current concepts relevant to orthotopic topic liver transplantation. In this, the second article, they discuss the vascular and biliary complications of the operation, and the third article will cover the medical complications.