Eva T. Heuser

A histologic evaluation of mixed connective tissue disease in childhood

Abstract Mixed connective tissue disease (MCTD) includes features of scleroderma, dermatomyositis and systemic lupus erythematosus (SLE), and has speckled antinuclear antibodies (ANA) and high titers of anti-RNP antibodies. There are no comprehensive investigations of its histopathology. We have followed 15 children with MCTD, of whom four have died (mean disease duration prior to death 5.4 years). The immediate causes of death were pneumococcal sepsis (two patients), meningococcal sepsis (one patient) and uncontrollable thrombocytopenia (one patient). Material from the three available autopsies and five renal biopsies was reviewed. The most prominent histopathologic feature was widespread proliferative vascular lesions including intimai vascular change in 31 of 58 organs (53 per cent) and medial vessel wall thickening in nine organs (16 per cent). Systemic hypertension was absent; the normal vascular responses to aging could be excluded. Inflammatory infiltrates, often with prominent plasmacytosis, were present in 26 of 58 organs (45 per cent), but fibrinoid vascular change (9 per cent) and fibrosis (14 per cent) were rare. Eight renal specimens all showed some degree of glomerulonephritis; membranous change was present in three, and six showed significant vascular sclerosis. The histopathology of MCTD is superficially similar to systemic sclerosis, but it may be distinguished by less frequent fibrosis, the frequency of organs with intimal vascular change, and a predilection for intimai thickening of large arteries including coronary, pulmonary, renal and aortic. A distinctive replacement of muscle layers by hyaline in the gastrointestinal tract, and an unusual nodular hyperplasia of the thymic medulla were also observed and may be unique features of MCTD. The findings from this study suggest an immunologic basis for MCTD different from those postulated for other rheumatic diseases, and strongly suggest that adjustment of morbidity and mortality expectations for MCTD are necessary.

A fatal case of inappropriate adh secretion induced by cyclophosphamide therapy

Cyclophosphamide is used extensively to treat malignancies. A 5‐year‐old boy with stage IV neuroblastoma is described who developed a fatal syndrome of inappropriate antidiuretic hormone (ADH) secretion after high dose cyclophosphamide therapy.

Focal glomerulosclerosis and renal transplantation

Eighteen patients with corticosteroid-resistant nephrotic syndrome developed end-stage renal disease and received one or more renal allografts. The lesion of focal segmental glomerulosclerosis and/or of focal glomerular obsolescence was demonstrable in the native kidneys of each patient. Following transplantation, nephrosis developed in three recipients. Two recipients developed nephrosis at two weeks and nine months posttransplant in association with rejection; the lesion of FGS was present in association with chronic rejection. Only one recipient developed recurrence of nephrosis and FGS unrelated to rejection. This was manifested by immediate onset of nephrosis in two successive allografts and histologic evidence of the lesion of FGS. The immediate recurrence in successive allografts suggests a circulating factor responsible for the renal lesion in this patient and indicates a separate etiology for a small number of patients with corticosteroid-resistant nephrosis and FGS.

Thrombosis, nephrosis, and corticosteroid therapy

Thromboemboli occurred in 5 children receiving corticosteroid therapy for idiopathic nephrosis; 3 had fatal pulmonary thromboemboli and 2 survived peripheral involvement. The factors related to thromboemboli in children with nephrosis are considered and discussed in relationship to the known and possible effects of corticosteroid therapy.

Prevalence of medium-chain acyl-coenzyme A dehydrogenase deficiency in the sudden infant death syndrome.

Disorders of fatty acid beta-oxidation have been suggested as playing a significant role in the sudden infant death syndrome (SIDS). To elucidate the role of medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency in SIDS, we identified all cases of SIDS occurring in Los Angeles County between January 1986 through December 1991. A total of 1304 SIDS deaths were identified; tissue samples were collected in 1236 cases (94.8%). Extraction of DNA was successful in 1224 tissue samples (93.9%), which were examined for the presence of the G985 mutation, identified as occurring in more than 88% of affected cases of MCAD deficiency. Three heterozygotes and no homozygotes were identified; this incidence does not differ from that reported in the general population. Review of the pathologic specimens from the identified heterozygotes and from 18 ethnic-, age-, and sex-matched control subjects revealed significant fatty infiltration of all organs examined in one of the three heterozygotes and in none of the control subjects. We conclude that MCAD deficiency does not play a significant role in the causation of SIDS.

Hypertension secondary to a renin-producing juxtaglomerular cell tumor

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Lymphomatoid granulomatosis-like lesions in a child with leukemia in remission

This case report describes an eight year old leukemic child who was in remission for four and one-half years and showed hypogammaglobulinemia and deficient leukocyte chemotaxis and migration. She developed pulmonary lesions with laryngeal and tracheobronchial disease and died from pulmonary hemorrhage. The lesions found at autopsy were lymphomatoid granulomatosis-like, but were atypical in their anatomic distribution, behavior, and histologic features.

Infantile polycystic disease of the kidneys and Ehlers-Danlos syndrome in an 11-year-old patient.

region in Eastern Europe. Because of these observations, a reluctance to make the diagnosis of familial dysautonomia in non-Jews has developed, as this patient illustrates. Although several claims of non-Jewish cases exist in the world literature, 7. ~ we have found none which fulfill Riley and Moores criteria? and are impressed that a number of these reports do not attempt to trace ancestry. Because of the demands that a child with dysautonomia imposes on a family, and the special nature of the problems encountered as the child grows older, prompt recognition of the disease and family education are vital. The autosomal recessive inheritance, at least among Ashkenazi Jews, makes genetic counselling equally important. Early diagnosis should therefore be made whenever possible. With a clinical picture as distinctive as that illustrated by the subject of this report, we feel that the diagnosis of familial dysautonomia can be established despite the absence of Jewish ancestry. Although this patient conforms to the phenotypic criteria for familial dysautonomia, it must be recognized that his disease may not necessarily be genotypically identical with the disorder occurring in the Ashkenazi Jew.

CHANGES IN GLOMERULAR BASEMENT MEMBRANE(GBM) ANTIGEN(S) WITH AGE AND DISEASE

GBM of patients with Alport Syndrome(AS) does not bind anti-GBM (McCoy et al, Lab Invest 3:19, 1976). Diagnostic use of staining kidney biopsies of AS suspect children with antiGBM was evaluated. Kidneys of 21 autopsied patients without renal disease (Groups I-III) and 3 patients with AS (with characteristic electron microscopic lesions) were treated with serum of a patient with strong antiGBM, then with fluorochromed anti IgG. Results were as follows:Young infants, like AS patients, appear to lack GBM antigen(s) normally present in older children and adults. Normal GBM increases from 950 Å at birth to 2844 Å by 3 years. Whether adult components are superimposed on fetal GBM or fetal GBM is replaced by adult GBM components is unknown. Failure of GBM to bind antiGBM is not diagnostic of AS in young infants, but is useful in older patients. These data may also partly explain absence of antiGBM nephritis in young children.