Inactivation of WT1 in nephrogenic rests, genetic precursors to Wilms' tumour.

Nephrogenic rests consist of foci of primitive renal cells, typically microscopic, that are found within the normal kidney tissue of children with Wilms' tumour. To study the relationship between nephrogenic rests and the associated tumours, we screened these lesions for mutations in the 11p13 Wilms' tumour suppressor gene, WT1. In two cases in which the Wilms' tumour contained a somatic WT1 mutation, the nephrogenic rest had the identical mutation. Nephrogenic rests and Wilms' tumours are therefore topographically distinct lesions that are clonally derived from an early renal stem cell. Inactivation of WT1 appears to be an early genetic event which can lead to the formation of nephrogenic rests, enhancing the probability that additional genetic hits will lead to Wilms' tumour.

Hepatic Hilar Lymph Node Reactivity at Kasai Portoenterostomy for Biliary Atresia: Correlations With Age, Outcome, and Histology of Proximal Biliary Remnant.

We hypothesized that if infection is the proximate cause of congenital biliary atresia, an appropriate response to antigen would occur in lymph nodes contiguous with the biliary remnant. We compared the number of follicular germinal centers (GC) in 79 surgically excised hilar lymph nodes (LN) and 27 incidentally discovered cystic duct LNs in 84 subjects at the time of hepatic portoenterostomy (HPE) for biliary atresia (BA) to autopsy controls from the pancreaticobiliary region of non-septic infants >3 months old at death. All 27 control LN lacked GC, a sign in infants of a primary response to antigenic stimulation. GC were found in 53% of 106 LN in 56 of 84 subjects. Visible surgically excised LN contiguous with the most proximal biliary remnants had 1 or more well-formed reactive GC in only 26/51 subjects. Presence of GC and number of GC/LN was unrelated to age at onset of jaundice or to active fibroplasia in the biliary remnant but was related to older age at HPE. Absent GC in visible and incidentally removed cystic duct LNs predicted survival with the native liver at 2 and 3 years after HPE, P = .03, but significance was lost at longer intervals. The uncommon inflammatory lesions occasionally found in remnants could be secondary either to bile-induced injury or secondary infection established as obstruction evolves. The absence of consistent evidence of antigenic stimulation in LN contiguous with the biliary remnant supports existence of at least 1 major alternative to infection in the etiology of biliary atresia.

Studies on the pathogenesis of pigment gallstones in hemolytic anemia: description and characteristics of a mouse model.

The pathogenesis of hemolysis-induced gallstones was studied in mice with a hereditary hemolytic disease called normoblastic anemia (genotype nb/nb) and in their normal controls (genotype +/+). Infrared spectroscopy demonstrated that spontaneously formed gallstones from nb/nb mice were nearly identical to stones from patients with chronic hemolysis as the result of sickle cell disease, and both mouse and human stones strikingly resembled synthetic calcium bilirubinate. 57% of 115 nb/nb mice, but none of 109 control mice, developed calcium bilirubinate pigment gallstones (P < 0.001). The incidence of luminal gallstones in nb/nb mice was both sex and age dependent. Female nb/nb mice formed stones twice as frequently as male nb/nb mice (P < 0.001). Before 6 mo of age neither sex developed stones, but thereafter the incidence of stones increased with age. Neither hematocrit, reticulocyte count, nor total plasma bilirubin values, were useful in distinguishing between nb/nb mice with or without gallstones. In gallbladder bile, nb/nb mice with gallstones had higher concentrations of hydrogen ion, total bilirubin, calcium, and bile acids than nb/nb mice without stones. Although total unconjugated bilirubin was similar in both nb/nb groups, the ionized fraction of unconjugated bilirubin was higher in bile from nb/nb mice without stones than those with stones. In nb/nb mice, neutral mucin plugs and pigment concentrations were observed histologically in the glandular crypts of the gallbladder in 33% of nb/nb mice without stones and in 80% of nb/nb mice with luminal stones. This suggested that luminal pigment stone disease in mice with hemolysis may be preceded by microscopic precipitation of calcium bilirubinate in the glandular crypts of the gallbladder. These precipitates may then migrate into the lumen and grow by accretion.

What more can we learn from muscle histopathology in children with dermatomyositis/polymyositis?

OBJECTIVE: To correlate disease course and complications in children with juvenile dermatomyositis (JDM) and polymyositis (JPM) with specific features of muscle pathology on biopsy. METHODS: This is a retrospective cohort analysis of 59 children diagnosed with JDM or JPM between 1965 and 1998 and followed at the Cincinnati Children's Hospital Medical Center (CCHMC) for a mean duration of 7.3 years (range 1.1-24.5 years). Disease course was characterized as limited, chronic non-ulcerative or chronic ulcerative, similar to previously defined disease course subtypes reported by Crowe et al.(1). All subjects had diagnostic muscle biopsies performed at CCHMC and had disease for at least two years' duration in order to classify their disease course as either limited or chronic. Features of muscle histopathology that were evaluated included loss of the intramuscular capillary bed, infarct, perifascicular myopathy, direct immunofluorescence (DIF) staining of the intramuscular vasculature and specifically, the locale of DIF staining, i.e., small arteries or capillaries. Disease complications that were assessed included calcinosis, contractures, muscle atrophy, lipodystrophy, gastrointestinal ulceration, cutaneous ulceration and death. Data analysis was completed using Chi-square or Fisher's exact tests and logistic regression modeling. RESULTS: Twenty-two children (37%) had limited disease, 24 (41%) had chronic non-ulcerative disease and 13 (22%) had chronic ulcerative disease. Neither loss of the intramuscular capillary bed nor perifascicular myopathy on muscle biopsy significantly correlated with disease course or the various complications evaluated in this study. DIF staining of intramuscular vessels overall was not significantly associated with clinical disease course, but the localization of DIF staining to intramuscular arteries (rather than to capillaries) was significantly associated with the outcome of chronic ulcerative disease. Nine of the 13 children with chronic ulcerative disease had DIF-arterial staining on muscle biopsy (69%), significantly greater than DIF-arterial staining in children with limited disease (32% had DIF-arterial staining) (p = 0.04), chronic non-ulcerative disease (8% had DIF-arterial staining) (p = 0.0002), and non-ulcerative disease overall (limited + chronic non-ulcerative disease groups combined) (20% had DIF-arterial staining), with p = 0.001. Additionally, lack of DIF-arterial staining on biopsy was significantly correlated with patients not having gastrointestinal ulceration (p = 0.002), cutaneous ulceration (p = 0.004) and/or death (p = 0.02) as disease-related complications. Infarct on muscle biopsy was significantly associated with the development of chronic ulcerative disease (p = 0.02), being present on biopsy in 23% of children with chronic ulcerative disease compared with none of the patients with chronic non-ulcerative disease and 4% of those with limited disease. Infarct on muscle biopsy correlated with the outcomes of death (p = 0.01) and gastrointestinal ulceration (p = 0.03), but not with the development of cutaneous ulceration (p = 0.18). CONCLUSION: DIF-arterial staining and infarct on muscle biopsy are significantly associated with the development of chronic ulcerative disease in JDM and JPM, while perifascicular myopathy and loss of the intramuscular capillary network are not associated with disease course. The presence of DIF-arterial staining and infarct on biopsy should suggest early use of second-line therapeutic agents to more quickly bring disease activity under control.

Multifocal nephroblastic neoplasia.

Among 23 patients with multifocal metanephric neoplasia were 14 patients with 43 grossly visible subcapsular tumorlets, 0.3-3.5 cm in diameter, that were apparently derived from nodular renal blastema. Tumorlets are defined as circumscribed lesions that are visible on the exterior surface of the kidney, produce either a raised nodule or, in a few instances, a shallow depression, and are independent of the main tumor(s). Most tumorlets displayed homogeneous epithelial maturation. A substantial minority of tumorlets retained a blastemic character and a few were histologically malignant. Tumorlets tended to be multiple and bilateral but were absent in 9 patients with multifocal disease, including 4 of 10 with bilateral tumors. About half the lesions that achieved tumorlet status, including those that gave rise to clinical tumors, underwent malignant transformation. Contralateral tumorlets should not be mistaken for metastasis and do not adversely affect prognosis. The incidence of neoplasia among young, close relatives of patients with multifocal disease appeared to be excessive, but no clear excess of major anomalies, hemihypertrophy, or minor genitourinary tract anomalies was revealed by a retrospective survey of hospital charts.

Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children.

In this study, we compare the morphological and genetic characteristics of 38 post-Chernobyl thyroid papillary carcinomas from Belarussian children 5-18 years old with those of 23 sporadic papillary carcinomas from the same age children without history of radiation exposure from Los Angeles and Cincinnati. Among radiation-induced tumors, solid variant of papillary carcinoma was found in 37%, follicular in 29%, typical papillary in 18%, and mixed and diffuse sclerosing variants in 8% each. In the sporadic group, a typical papillary pattern was prevalent in 70%, follicular in 17%, diffuse sclerosing variant in 9%, and solid in 4%. In both groups, the prevalence of ret rearrangements was high, but the frequency of specific types of rearrangement was significantly different. Among radiation-induced tumors, ret/PTC3 was found in 58%, ret/PTC1 in 16%, and ret/PTC2 in 3%, whereas among sporadic tumors, ret/PTC1 was found in 47% (P < 0.05), and ret/PTC3 was found in 18% (P = 0.01). The morphological variants of papillary carcinoma showed different prevalence of the specific types of ret rearrangement. Seventy-nine % of solid variant tumors had ret/PTC3, whereas only 7% had ret/PTC1 (P = 0.0007). Among typical papillary tumors, ret/PTC1 was found in 38%, ret/PTC3 in 19%, and ret/PTC2 in 5%. Thus, ret rearrangements are highly prevalent in pediatric papillary carcinomas from children exposed to radiation and in those occurring sporadically. However, the types of ret/PTC vary between these two populations, with ret/PTC3 present more commonly in post-Chernobyl tumors. Furthermore, solid variants have a high prevalence of ret/PTC3, whereas typical papillary carcinomas do not, suggesting that the different types of ret rearrangement confer neoplastic thyroid cells with distinct phenotypic properties.

Echocardiographically determined left ventricular mass index in normal children, adolescents and young adults.

Left ventricular hypertrophy is an important diagnostic and prognostic finding in children with cardiovascular disease, but there are currently no well established criteria for its determination by M-mode echocardiography. Three hundred thirty-four subjects, aged 6 to 23 years, who were free of cardiovascular disease were studied. Left ventricular mass was calculated using echocardiographic measurements in a regression equation for left ventricular mass. Intraobserver (r = 0.96, p less than 0.01) and interobserver (r = 0.89, p less than 0.01) variability were low. To anatomically validate the echographic formula for left ventricular mass, left ventricular measurements made at autopsy were inserted into the formula. Mass was then calculated and compared with the actual mass. There was a strong correlation between the calculated and the measured left ventricular mass (r = 0.89, p less than 0.01). Left ventricular mass was not statistically related to race, but it was strongly associated with gender (p less than 0.001). It was strongly correlated with height (r = 0.82 for males, r = 0.71 for females) and body surface area (r = 0.83 for males, r = 0.74 for females). Echocardiographic criteria for left ventricular hypertrophy in children and adolescents, based on the 95th percentile, for left ventricular mass, left ventricular mass corrected for body surface area and left ventricular mass corrected for height are, respectively: 184.9 g, 103.0 g/m2 and 99.8 g/m for males and 130.2 g, 84.2 g/m2 and 81.0 g/m for females.(ABSTRACT TRUNCATED AT 250 WORDS)

Nonabsorptive hydrocephalus associated with nephropathic cystinosis.

A child with nephropathic cystinosis developed seizures and coma. CT showed prominent sulci and slight ventricular enlargement. Nuclear cisternogram was normal. Despite successful renal transplantation and treatment of hypothyroidism, neurologic recovery was poor. CT and nuclear cisternogram 5 months later showed moderate panventricular and subarachnoid space enlargement and abnormal ventricular isotope retention. Ventriculoperitoneal shunt placement was followed by improved intellectual function, resolution of pyramidal tract signs, and control of seizures. Anisotropic crystals consistent with cystine were demonstrated in biopsy samples of arachnoid and cerebral cortex. Nonabsorptive hydrocephalus may have resulted from deposition of cystine in the meninges.

Visualization of alcohol-induced rhabdomyolysis: a correlative radiotracer, histochemical, and electron-microscopic study.

Technetium-99m diphosphonate was used to visualize the extent of alcohol-induced rhabdomyolysis and its resolution. Transient secondary hyperparathyroidism was documented. Histological and biochemical analyses of skeletal muscle obtained at biopsy 6 days postscan and 9 days after the onset of the illness did not show abnormal calcium content.

Liver disease caused by disorders of bile acid synthesis.

Bile acid synthetic defects are uncommon disorders that cause progressive cholestatic liver disease that is often lethal in infancy or early childhood. Five specific primary defects have been described. Diagnosis is based on mass spectrometry of urine and serum. Pathogenesis of liver injury is related to persistent reduction in levels of normal bile acids and accumulation of abnormal, potentially hepatotoxic, intermediaries. Sites of injury are the liver cell, the bile canaliculus, and the smallest bile ductules. The interlobular bile ducts are normal. The liver lesion is progressive chronic hepatitis with an especially high incidence of GCT in patients who present in infancy. Bile acid replacement therapy is usually effective in arresting the liver injury. Regression of liver damage has been documented during treatment of patients who were diagnosed early in life. Because bile acid synthetic disorders are the only cholestatic diseases of infancy in which GCT of hepatocytes is consistently present, the author suggest that the injury responsible for GCT may be specific for toxic bile acids. Accordingly, immaturity of the bile acid synthetic pathway may render many otherwise normal infants vulnerable to transient "neonatal hepatitis" with GCT in a broad range of cholestatic disorders.

Pathological findings in Gaucher disease type 2 patients following enzyme therapy.

The pathological outcomes following intravenous acid beta-glucosidase (alglucerase) infusions were compared in two siblings with Gaucher disease type 2, the acute neuronopathic variant. In case 1 enzyme infusions (four doses at 7 months) had no effect when severe progressive visceral and neuronopathic disease were present. Death from progressive disease occurred at 9 months. Case 2 was prenatally diagnosed. Enzyme infusions were initiated presymptomatically at 4 days of age and continued until death at 15.2 months. Development progressed satisfactorily, albeit at a slower than normal rate until age 10 months when progressive brain stem involvement became evident. Death occurred after slowly progressive brain stem dysfunction, but gross motor and cognitive skills were nearly normal. Postmortem light and electron microscope (EM) studies in both cases showed typical central nervous system (CNS) findings and massive infiltration of the lungs and lymph nodes by Gaucher cells. The liver, spleen, and bone marrow, except that in the temporal bone, in case 2 were normal. These studies show that enzyme therapy may slow but does not prevent the development of lethal CNS disease in Gaucher disease type 2, even when initiated presymptomatically. These findings also indicate the nonuniformity of tissue responses to enzyme therapy implying the existence of therapeutically inaccessible compartments that, in less severe variants, may create unexpected long-term disease complications.

The internal carotid artery siphon in children and adolescents.

We observed significant lesions of the carotid artery siphon in two young subjects with fatal stroke. Because stroke in children and adolescents is uncommon and poorly understood, we examined the internal carotid artery in the 'siphon' of the skull in 24 unselected, but nearly consecutive autopsies. The age range was 10 days to 38 years, with 11 males and 13 females, six blacks, and 18 whites. In no case was stroke the cause of death. Intimal lesions of two types were found in the carotid siphon of all cases. (1) The first was focal splitting and/or duplication of the internal elastic lamina with variable proliferation of smooth muscle. The resulting 'fibrous' plaques or cushions, when severe, were usually found at natural bends in the artery. The number and severity of this type of lesion increased with age, but there were no differences in severity or distribution when compared by sex, race, or mode of death. (2) The second was internal elastic calcification which was found in all cases older than 9. This was increasingly severe with age. Although the frequency of the vascular lesions was surprisingly high, the relationship of either type to dissecting aneurysm or other stroke lesion remains unclear.

Severe perinatal liver disease and Down syndrome: an apparent relationship.

Down syndrome (DS) is not usually thought of in association with significant infantile liver disease. We present clinical and histopathologic data from 10 patients with DS who presented with severe liver disease at birth or within the first few weeks of life, and summarize the findings of eight previously reported cases. The liver disease was fatal in all but one case. Diffuse lobular fibrosis surrounding proliferating ductular elements and residual hepatocytes characterized the pathologic findings in the liver in all patients. A large number of megakaryocytes were present in the liver in nine of 12 patients. The phenotype of "perinatal hemochromatosis" was documented in eight of nine cases in which the presence of iron was investigated. Since only a fraction of the patients with this phenotype have DS, the patients we describe seem to represent a relatively well-defined subset of the perinatal hemochromatosis phenotype. The existence of such a subset suggests that the perinatal hemochromatosis phenotype does not represent a single etiopathogenetic disorder. The association between DS, megakaryocytic infiltrates in the liver, and fatal subacute/chronic liver disease gives rise to the speculation that fibrosis-promoting factors and/or metabolic abnormalities, such as those resulting from a gene dosage effect, may play a role in the genesis of the liver disease, perhaps due to a particular susceptibility of fetal liver.

The large window ductus: a surgical trap.

A rare window type of patent ductus arteriosus is reported that was large (15 mm in maximal transverse dimension) but had virtually no length and hence was externally invisible. The smaller aortic isthmus (4 mm in diameter), which was intrapericardial, was mistaken for the ductus and was inadvertently clip-occluded, leading to death. After a specific diagnosis is made, the large window ductus should be patched on cardiopulmonary bypass with a transpulmonary approach.

Intracranial hemorrhage in premature infants: sonographic-pathologic correlation.

Spontaneous intracranial hemorrhage is the most common central nervous system abnormality in premature infants. In this report the cranial sonographic and pathologic findings of 25 autopsied premature infants are correlated. The presence and size of subependymal, intraventricular, and intraparenchymal hemorrhage were well documented by sonography. Cerebellar, choroid plexus, and cortical hemorrhage, though less frequent, were also recognized. There was good correlation as to the presence and degree of hydrocephalus. Prominent subarachnoid spaces on sonography correlated poorly with subarachnoid hemorrhage at autopsy and may be a normal variant in the premature infant. Anoxic brain damage was not diagnosed early by sonography unless associated with hemorrhage, but diffuse brain atrophy with hydrocephalus exvacuo was detected by sonography.

Wilms' tumor and related abnormalities in the fetus and newborn.

Mesoblastic nephroma, a benign tumor, is the most common renal neoplasm in neonates. Wilms' tumor (WT) may occur in newborn infants, but is more common in older children. The molecular genetics of WT involves one or more genes located on Chromosome #11 and probably other locations not yet elicidated. Germline mutations cause less than 5% of WTs; most WTs are sporadic. Precursor lesions to WT called nephrogenic rests may be detected before evolution to WT by imaging studies. Developmental anomalies comprising several different syndromes are associated with nephrogenic rests and predisposition to WT. Prospective surveillance for WT may be feasible in high risk infants identified on the basis of physical findings followed by testing for predisposing gene defects and periodic imaging of the kidneys and other organs at risk until the period of risk has ended.

Formation of intracerebral cavernous malformations after radiation treatment for central nervous system neoplasia in children.

OBJECT: Radiation is a common treatment modality for pediatric brain tumors. The authors present a retrospective review of six children who developed cerebral cavernous malformations after they underwent radiation treatment for central nervous system (CNS) neoplasia and propose two possible models to explain the formation of cavernous malformations. METHODS: Three boys, aged 13, 9, and 17 years, suffered intracerebral hemorrhages from cerebral cavernous malformations 87, 94, and 120 months, respectively, after they received whole-brain radiation therapy (WBRT) for acute lymphocytic leukemia. A 10-year-old girl and a 19-year-old man developed temporal lobe cavernous malformations 46 and 48 months, respectively, after they received radiation therapy for posterior fossa astrocytomas. A 12-year-old girl developed a temporal lobe cavernous malformation 45 months after WBRT was administered for a medulloblastoma. In all of these cases the cavernous malformation appeared in the irradiated field, was not known to be present prior to radiation therapy, and developed after a latency period following treatment. The incidence of cavernous malformations in these patients suggests that children who undergo radiation therapy of the brain may have an increased risk of hemorrhage. CONCLUSIONS: Two possible models may explain the formation of cavernous malformations following brain radiation in these patients. First, the cavernous malformations may form de novo in response to the radiation. Second, the cavernous malformations may have been present, but radiographically occult, at the time of radiation therapy and may have hemorrhaged in response to the radiation. The authors conclude that cavernous malformations may develop after brain radiation and propose a possible mechanism for this formation.

Innominate artery compression of the trachea: current concepts.

One common vascular anomaly that causes airway obstruction in neonates and infants is innominate artery compression of the trachea. A great deal of controversy exists regarding the effect of this anatomic variant on symptom production. Several cases are presented that demonstrate the unique features of innominate artery compression of the trachea: 1. Innominate artery compression can occur in adolescent patients. 2. Flow volume loops are an effective method of documenting airway compromise in this condition. 3. Exercise intolerance should be considered as a relative indication for surgical intervention in these patients. 4. Reimplantation of the innominate artery is a viable surgical alternative in the treatment of affected patients. 5. Telescopic bronchoscopy during surgical correction of this condition will ensure that there has been successful correction of the tracheal compression. 6. Urgent repair is advocated in patients who experience periods of apnea.

Prolonged myasthenic syndrome after one week of muscle relaxants.

A child developed severe, generalized muscle weakness which persisted for 6 weeks, after receiving muscle relaxants for 1 week while requiring ventilator support. Electrodiagnostic studies indicated a presynaptic disorder of the neuromuscular junction which improved with high-frequency stimulation, similar to findings in Lambert-Eaton syndrome. Muscle specimens exhibited neurogenic targetoid fiber atrophy. Ultrastructure of the neuromuscular junction indicated terminal axon degeneration and atrophy with depletion of the secretory vesicles. Most reported patients with post-ventilator paresis have received steroids and muscle relaxants; muscle weakness commonly has been brief and attributed to steroids. We believe that this reversible myasthenic syndrome probably represents neurotoxicity due to high doses of steroidal nondepolarizing blocking agents; however, available data are insufficient to resolve this controversy.