Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): evidence for heterogeneity.

Byler disease (ByD) is an autosomal recessive disorder in which cholestasis of onset in infancy leads to hepatic fibrosis and death. Children who have a clinically similar disorder, but are not members of the Amish kindred in which ByD was described, are said to have Byler syndrome (ByS). Controversy exists as to whether ByD and ByS (subtypes of progressive familial intrahepatic cholestasis [PFIC]) represent one clinicopathological entity. The gene for ByD has been mapped to a 19-cM region of 18q21-q22. PFIC caused by a lesion in this region, including ByD, can be designated PFIC-1. Examination of haplotypes in siblings with ByS in two unrelated non-Amish families showed that the gene(s) responsible for their disorder(s) did not lie in the PFIC-1 candidate region. On light microscopy and transmission electron microscopy (TEM), liver tissue differed between Amish children with PFIC-1, who had coarsely granular bile and at presentation had bland intracanalicular cholestasis, and the children with ByS in the two non-Amish families, who had amorphous or finely filamentous bile and at presentation had neonatal hepatitis. Bile acid composition of bile also differed: In the Amish children with PFIC-1 and in one ByS family, the proportional concentration of chenodeoxycholic acid (CDCA) in bile was low compared with normal bile; in the other ByS family, it was only slightly reduced. Genetic analysis and light microscopy and TEM of liver may help distinguish PFIC-1 from other forms of ByS.

Association of Epstein-Barr virus with leiomyosarcomas in young people with AIDS.

BACKGROUND: Children with the acquired immunodeficiency syndrome (AIDS) have an unusually high incidence of smooth-muscle tumors (leiomyomas and leiomyosarcomas) in addition to malignant lymphomas. We tested the hypothesis that the smooth-muscle tumors in these children are associated with the Epstein-Barr virus (EBV). METHODS: Tissue specimens of five leiomyosarcomas and two leiomyomas from six children with AIDS were studied for evidence of the human immunodeficiency virus (HIV) and EBV by in situ hybridization and quantitative polymerase chain reaction (PCR). Comparison specimens included samples of leiomyosarcoma and leiomyoma from HIV-negative children. EBV clonality of leiomyosarcomas was determined by Southern blot analysis with oligonucleotide probes for EBV terminal-repeat fragments. Tumor specimens were tested by immunoperoxidase staining for infiltration by B lymphocytes and expression of the EBV receptor. Serologic testing for EBV was performed. RESULTS: In situ hybridization showed EBV genomes in all muscle cells of the five leiomyosarcomas and the two leiomyomas from the six HIV-infected children. Quantitative PCR demonstrated strikingly high levels of EBV in tumor tissue, with as many as 4.3 genome copies per cell. Two colonic leiomyosarcomas obtained from different sites at different times from one patient contained different episomal EBV clones, signifying the presence of distinct monoclonal EBV-related tumors. We found biclonal EBV infection in the leiomyosarcoma of another patient. No EBV was detected in normal muscle or tumor specimens from HIV-negative patients. Immunostaining for the EBV receptor was strongly positive in six of the seven leiomyomas and leiomyosarcomas from the patients with AIDS. CONCLUSIONS: EBV can infect smooth-muscle cells, at least in patients with AIDS, and it may contribute to the pathogenesis of leiomyomas and leiomyosarcomas in children with AIDS. EBV seems to play no part in smooth-muscle tumors in HIV-negative children.

Disseminated leiomyosarcoma in a child with acquired immune deficiency syndrome.

A child with disseminated leiomyosarcoma and acquired immune deficiency syndrome (AIDS) is reported. She was originally believed to have peptic ulcer disease by radiographic and endoscopic evaluation but was found subsequently to have hypergastrinemia, hypochlorhydria, and a smooth muscle tumor. Leiomyosarcoma in children and its evolution in AIDS are discussed.

Rheumatic heart disease in a patient with acquired immunodeficiency syndrome.

Acute rheumatic heart disease (RHD) with Aschoff nodules and biventricular dilation was diagnosed at autopsy in a patient with acquired immunodeficiency syndrome who died of pneumonia due to Pneumocystis carinii. The relationship of acute RHD and human immunodeficiency virus-associated immune deficiency is discussed.

Sarcoidosis of the uterus.

The present case of sarcoidosis of the uterus and the previously reported cases are reviewed. Uterine sarcoidosis is usually detected during the investigation of abnormal uterine bleeding in patients with prior evidence of sarcoidosis in another site. However, in several of the reviewed cases, either the uterus was the site of the initial diagnosis of sarcoidosis or its involvement was detected soon afterward. When hysterectomies were performed on patients with endometrial involvement, the myometrium was usually found to contain nonnecrotizing epithelioid granulomas. By contrast, uterine tuberculosis usually spares the myometrium. The differential diagnosis between uterine sarcoidosis and uterine tuberculosis is discussed.

Primary lymphoma of the central nervous system in children with acquired immunodeficiency syndrome.

Three children with acquired immunodeficiency syndrome and primary lymphoma of the CNS are described. All three children had clinical signs of focal mass lesions and progressive neurologic deficits. In one child the deterioration was extremely rapid. New lesions appeared on serial CT scans every few days, simulating an infectious process and leading to death within 3 weeks. Results of neuroradiologic studies in these patients demonstrated multicentric lesions that were often periventricular. On CT scans, the lesions were hyperdense before contrast and were enhanced with contrast medium. Double-dose delayed contrast CT scans and magnetic resonance imaging studies were more sensitive in indicating additional lesions. Histologically, all three tumors were B cell neoplasms; two lymphomas were large cell type, whereas one was small cell, noncleaved (Burkitt-like). Primary CNS lymphoma occurred with an incidence of 1/26 (4%) in our autopsy series and 3/100 (3%) of all pediatric cases of human immunodeficiency virus-type 1 infection, living and dead, that have been seen at the Children's Hospital of New Jersey. By comparison, opportunistic and reactivated latent CNS infections were less common in this same population and never appeared clinically as mass lesions. Therefore, in our experience, primary lymphoma is the most common cause of focal or multifocal mass lesions in the brains of children with acquired immunodeficiency syndrome. This tumor may be radiosensitive. In most cases, early biopsy is probably necessary to establish the diagnosis.

Syndromes of cardiovascular malformations induced by copper citrate in hamsters.

Pregnant golden hamsters were injected intraperitoneally on the morning of the eighth day of gestation with a solution of copper citrate (2.7 mg/kg) or deionized water. Embryos were removed from the mothers by laparotomy on the 12th and 13th days of gestation, serially sectioned through the thorax, and examined for cardiac malformations. Twenty-one of the 37 edematous embryos from copper-treated mothers were affected with a total of 58 major cardiac anomalies. Sixteen of these embryos were affected with double outlet right ventricle in association with a membranous ventricular septal defect, two embryos contained hearts with overriding aortas, and three embryos were affected with isolated ventricular septal defects. Eleven of the 16 embryos with double outlet right ventricle were also affected with pulmonary trunk hypoplasia. The concept that these cardiac anomalies arise from a common pathogenetic basis is supported by the present model.

Copper-induced heart malformations in hamsters.

The injection of copper citrate into pregnant golden hamsters induces a specific pattern of cardiovascular malformations in their embroys. The syndrome consists of double-outlet right ventricle, pulmonary hypoplasia and a ventricular spetal defect.