Solitary rectal ulcer syndrome in children. A report of three cases.

Solitary rectal ulcer syndrome (SRUS) is a rare condition in children. It is well recognised in the adult literature. We report our experience with 3 patients; two boys presented at a very young age (18 and 24 months, respectively) with a clinical picture simulating inflammatory bowel diseases. The other patient was a fifteen-year-old girl presenting with severe rectal stricture as a result of the syndrome, which is the first to be reported in the paediatric literature.

Corroboration of in utero MRI using post-mortem MRI and autopsy in foetuses with CNS abnormalities.

AIMS: To corroborate the findings of in utero magnetic resonance imaging (MRI) with autopsy and post-mortem MRI in cases of known or suspected central nervous system (CNS) abnormalities on ultrasound and to compare the diagnostic accuracy of ante-natal ultrasound and in utero MRI. METHODS: Twelve pregnant women, whose foetuses had suspected central nervous system abnormalities underwent in utero MRI. The foetuses were imaged using MRi before autopsy. The data were used to evaluate the diagnostic accuracy of in utero MRI when compared with a reference standard of autopsy and post-mortem MRI in 10 cases and post-mortem MRI alone in two cases. RESULTS: The diagnostic accuracy of antenatal ultrasound and in utero MRI in correctly characterizing brain and spine abnormalities were 42 and 100%, respectively. CONCLUSION: In utero MRI provides a useful adjuvant to antenatal ultrasound when assessing CNS abnormalities by providing more accurate anatomical information. Post-mortem MRI assists the diagnosis of macroscopic structural abnormalities.

Differential growth rates of the cerebellum and posterior fossa assessed by post mortem magnetic resonance imaging of the fetus: implications for the pathogenesis of the chiari 2 deformity.

PURPOSE: To evaluate post mortem magnetic resonance imaging of the fetus to provide data on the rate of growth of the cerebellum, bony posterior fossa, supratentorial bony compartment and cerebrum. MATERIAL AND METHODS: Twenty fetuses subsequently shown to have normal brain and spines on autopsy were studied using MRI post mortem. MRI from 20 normal pediatric brain examinations in children aged 6 years or younger were studied for comparison. Post mortem MRI was performed using a high-resolution fast spin echo technique providing T2 weighted images. The area of the cerebellar vermis, posterior fossa, supratentorial skull cavity and cerebral hemispheres was measured in the sagittal plane in all cases. These measurements were compared over the age ranges studied. RESULTS: We have shown that there are differences in the rate of growth and the apparent commencement of growth between the structures under study. The cerebellum appeared to start its significant growth at 16.5 weeks with a rate of 16 mm2/week throughout pregnancy, while the cerebral hemisphere appeared to commence significant growth at 13 weeks at a rate of 184 mm2/week throughout pregnancy. This is in contrast to the bony posterior fossa, whose growth paralleled the supratentorial bony compartment at all ages studied. CONCLUSION: We interpret our findings as showing relatively late commencement of cerebellar growth compared to the cerebral hemispheres, whereas the growth of the bony posterior fossa appears to be in advance and independent of cerebellar growth. Our results support the hypothesis that posterior fossa development depends on raised hydrostatic pressure in the CSF containing structures of the posterior fossa. When this mechanism fails, as in some cases of myelomeningocoele, a small posterior fossa is formed which characterizes the Chiari 2 malformation.

Elevated serum concentrations of beta-tryptase, but not alpha-tryptase, in Sudden Infant Death Syndrome (SIDS). An investigation of anaphylactic mechanisms.

BACKGROUND: Sudden Infant Death Syndrome, (SIDS) or cot death, remains the most common category of post-perinatal death in the UK. By definition, the cause of death is unknown, but a long-standing theory is that some of these deaths could be the result of anaphylaxis. OBJECTIVE: To investigate the potential contribution of anaphylactic mechanisms to deaths in infancy by determining relative levels of alpha- and beta-tryptases and both total and allergen-specific IgE in sera from groups of infants whose deaths were attributed to SIDS or to other causes. METHODS: Serum samples were collected at the time of post-mortem examination from infants whose death was classed as SIDS (n = 40) and from a comparison group in which cause of death had been established (n = 32). Serum tryptase concentrations were measured with a radioimmunoassay with monoclonal antibody G5 which detects primarily beta-tryptase or an ELISA with antibody AA5 which has equal sensitivity for alpha- and beta-tryptases. Levels of total IgE and IgE specific for casein, beta-lactoglobulin, house dust mite and moulds were determined. RESULTS: Analysis of the results of the two assays for tryptase indicated that levels of the beta-like tryptase (the form secreted on anaphylactic degranulation) were significantly higher in serum from infants with SIDS compared with those whose death was explained. There was no evidence for an increase in serum levels of alpha-tryptase (the variant secreted constitutively from mast cells). Total levels of serum IgE did not differ between the two groups and, reflecting the low circulating IgE concentrations in infancy, an elevation in IgE specific for the panel of allergens was not detected. CONCLUSIONS: In a proportion of SIDS victims there may be increased serum levels of beta-like tryptase, a marker for anaphylaxis. The failure to detect an increase in alpha-tryptase would suggest that mast cell hyperplasia is not a feature of cot death. The nature of the inciting agents remains unclear, but anaphylaxis deserves serious consideration as a possible cause of sudden death in infancy.

Small round cell tumor with biphenotypic differentiation and variant of t(21;22)(q22;q12).

A 14-year-old boy presented with a soft tissue swelling on the outer aspect of his left upper arm. Examination of the tumor by light microscopy showed a small round cell tumor with a rare focus of myogenic differentiation. Myogenic differentiation was confirmed on ultrastructural examination by immunohistochemistry and reverse transcriptase polymerase chain reaction (RT-PCR). Conventional G-banding and fluorescent in situ hybridization (FISH) demonstrated a complex variant of t(21;22)(q22;q12). By RT-PCR, the EWS-ERG fusion transcript was defined as type 9e. This tumor was unusual in that it showed characteristics of myogenic and neural differentiation, and contained a rearrangement of the EWS gene consistent with a diagnosis of Ewing's sarcoma. This supports the hypothesis that a class of biphenotypic childhood sarcomas, with features of myogenic and neural differentiation, exists that may be related to the Ewing's sarcoma family of tumors.

Relationship between histopathological features, MYCN amplification, and prognosis: a UKCCSG study. United Kingdom Children Cancer Study Group.

Histological sections from 231 patients with neuroblastoma were reviewed and morphological features and their relationship to age, stage, MYCN amplification (in 128 tumours by Southern analyses), and clinical outcome (based on Shimada risk grouping) determined. Stage 4 disease was associated with poorly differentiated and undifferentiated tumours (P = 0.001), an MKI of >2% (P< 0.001), and Shimada unfavourable histology (UHi) P< 0.0001. In univariate analysis MKI was significant in predicting a poorer relapse-free survival (RFS), low vs. intermediate and high (P< 0.001). Age, MYCN amplification, and Shimada UH also emerged as significant variables. There was a higher proportion of MYCN-amplified tumours with Shimada UH (P = 0.03), and this group had a decreased RFS (P = 0.002). In patients with Shimada FH, MYCN amplification did not significantly predict a poor prognosis. In those with stage 4 disease, Shimada classification was not significant in predicting survival (P = 0.97); the same was true for those over the age of 1 year (P = 0.66). In multivariate analysis, MYCN amplification and Shimada UH both emerged as independent prognostic factors. In conclusion, morphological features assigned some subsets of patients to prognostic risk groups. Most MYCN-amplified tumours have unfavourable histology and a poorer prognosis. However, in patients with stage 4 disease and those over the age of 1 year, other factors that may influence prognosis should be determined.

Comprehensive genetic and histopathologic study reveals three types of neuroblastoma tumors.

PURPOSE: To determine the relationship between multiple genetic features, tumor morphology, and prognosis in neuroblastoma. PATIENTS AND METHODS: The genetic alterations and morphologic features that underpin three histopathologic risk classifications were analyzed in 108 neuroblastoma patients. Tumors were subdivided into four groups based on the three most frequent and prognostically significant genetic alterations (17q gain, 1p deletion, and MYCN amplification), and all other genetic, morphologic, and clinical data were analyzed with respect to these groups. RESULTS: Our analyses identify three nonoverlapping tumor types with distinct genetic and morphologic features, defined here as types 1, 2, and 3. Type 1 tumors show none of the three significant genetic alterations and have good prognosis. Both type 2 (17q gain only or 17q gain and 1p del) and type 3 (17q gain, 1p del, and MYCN amplification) tumors progress. However, these tumor types are distinguished clinically by having significantly different median age at diagnosis and median progression-free survival (PFS). Multivariate analysis indicates that 17q gain is the only independent prognostic factor among all genetic, histopathologic, and clinical factors analyzed. Among histopathologic risk systems, the International Neuroblastoma Pathology Classification was the best predictor of PFS. CONCLUSION: Our results indicate that specific combinations of genetic changes in neuroblastoma tumors contribute to distinct morphologic and clinical features. Furthermore, the identification of two genetically and morphologically distinct types of progressing tumors suggests that possibilities for different therapeutic regimens should be investigated.

Child fatality associated with pathological features of histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease).

We report a case of histiocytic necrotizing lymphadenitis without granulocytic infiltration (Kikuchi-Fujimoto disease), diagnosed at necropsy in a 19-month-old child dying unexpectedly after a febrile illness. This is the youngest case with this disease that has been thus far reported. It is one of only two reported cases in which the patient died during the acute phase of the illness. Histological findings not unlike those seen in the lymph nodes were present at extranodal sites; this is the first case in which this feature has been described. In keeping with many other reported cases, it was not possible to identify an underlying etiology that might explain the morphologic changes.

Recognizable inherited syndrome of progressive central nervous system degeneration and generalized intracranial calcification with overlapping phenotype of the syndrome of Aicardi and Goutières.

Five boys and two girls from a large consanguineous British Muslim family of Pakistani origin are described. All presented from infancy to early childhood with progressive moderate to severe developmental delay, postnatal microcephaly, spastic quadriplegia, refractory seizures, and visual handicap. Cerebrospinal fluid (CSF) pleocytosis was present in three children. Neuroimaging with computerized tomography on three boys and a girl showed generalized cortical atrophy, dilatation of the lateral, third, and fourth ventricles, widening of the surface CSF spaces, hypoplasia of the posterior fossa structures, and multiple and solitary calcifications in the cerebral cortex and punctate calcifications involving basal ganglia, cerebellum, and the Sylvian fissure. Histopathological examination of the brain from three boys and one girl confirmed generalized cortical and cerebellar atrophy with widespread calcifications within the cortical grey and white matter, the basal ganglia, the cerebellum, and in some areas along the capillaries. Investigations excluded a possible nongenetic cause. Parental consanguinity favor autosomal recessive inheritance. This appears to be a recognizable syndrome overlapping the syndrome of Aicardi and Goutières (MIM 225750).

An animal model for copper-associated cirrhosis in infancy.

In Indian childhood cirrhosis (ICC) and related disorders of infancy, hepatic copper overload is associated with cirrhosis. Since copper administration alone has not been shown to induce cirrhosis in animals, synergy between copper and a second hepatotoxin has been suggested. This study investigates the ability of long-term exposure to copper and a pyrrolizidine alkaloid, retrorsine, to produce a model of copper-associated cirrhosis in rats. Groups of rat pups suckled on mothers fed 25 mg/kg diet retrorsine were weaned onto a diet containing 0.5 g/kg diet copper and retrorsine in varying dosage for 13 weeks. Histological similarities between the human disease and rats given copper with retrorsine 5 mg/kg diet included parenchymal destruction, fibrosis, nodular regeneration, and copper accumulation. There were significant histological differences from the human disorder, possibly attributable to inter-species variability or the critical timing or duration of exposure to hepatotoxins in the neonatal period. The hypothesis that ICC results from copper and a second hepatotoxin has not been disproved.

Determination of antimony in urine, blood and serum and in liver and lung tissues of infants by inductively coupled plasma mass spectrometry.

Methods are presented for the determination by ICP-MS of antimony in body fluids and tissues of infants. Urine, serum and whole blood specimens are prepared for analysis by simply diluting 200 microliters sample volumes (1 + 14) with water and adding indium as internal standard. Liver and lung tissues are digested using 16 M HNO3 either in open quartz vessels at 150 degrees C or in sealed vessels with microwave heating. The acid digests are diluted with water and indium is added as internal standard for ICP-MS measurements. All analyses were subjected to stringent internal quality control protocols. Accuracy was assessed by recoveries, repeated analyses and by analysis of NIST SRMs 1577a Bovine Liver and 1566a Oyster Tissue. Precisions of analyses were better than 5-10% in the ranges 0.1-0.3 microgram l-1 for urine, serum and blood; and at 7-25 ng g-1 in tissues. Detection limits were 0.7 ng g-1 in liver, 0.8 ng g-1 in lung, and 0.01 microgram l-1 in urine, serum and blood. The need to employ validated procedures for specimen collection and to give considerable attention to pre-analytical factors in order to avoid adventitious contamination with antimony is demonstrated.

The possible significance of cytomegaloviral parotitis in infant and early childhood deaths.

OBJECTIVE: To determine whether cytomegaloviral (CMV) parotitis reflects a disseminated disease that increases vulnerability to unexpected death. DESIGN: Necropsy-based cross-sectional study comparing incidences of brain stem microglial nodules and visceral lymphocytic infiltrates in patients with and without CMV parotitis. SUBJECTS: One hundred twelve infants and young children comprising a study group of 40 individuals with CMV parotitis (including 32 whose deaths remained unexplained) and two comparison groups comprising 40 explained and 32 unexplained deaths. MAIN OUTCOME MEASURES: Incidence and variation with age of brain stem microglial nodules and lymphocytic infiltrates in liver and kidneys. RESULTS: Brain stem microglial nodules and lymphocytic infiltrates in liver and kidneys are strongly associated with CMV parotitis; their incidence diminishes with increasing age. CONCLUSIONS: Disseminated disease frequently accompanies CMV parotitis in infants. The resolution of brain stem microglial nodules precedes that of parotitis. Active and previous brain stem involvement may increase vulnerability to unexpected death.

Splenic macrophages in preterm infants: a necropsy study.

AIMS: To study the frequency and nature of histiocytes in the splenic red pulp of infants who died following complicated immaturity/prematurity. METHODS: Twenty four preterm/immature infants were investigated. Frozen sections of formalin fixed splenic tissue were stained with Oil Red O. Paraffin wax sections from the same tissue were conventionally stained with haematoxylin and eosin. Immunohistochemistry was carried out for a number of macrophage markers. The administration of Intralipid was compared with the presence and extent of tissue macrophages. RESULTS: The spleens of 10 infants showed varying degrees of Oil Red O positivity ranging from mild to strong. In all these cases varying numbers of macrophages were confirmed in the splenic parenchyma in ordinary sections. The immunomarkers indicated that the histiocytes belonged to the macrophage phagocytic system. Of the 10 cases with splenic macrophages all had received Intralipid. Of those not receiving Intralipid none showed splenic macrophages. Seven had received Intralipid but did not have splenic macrophages; they had either only received small amounts of Intralipid or Intralipid was discontinued before death. CONCLUSIONS: Splenic macrophages are common at necropsy in immature/preterm infants. The macrophages are most lucidly demonstrated using Oil Red O staining in frozen sections. There is a strong association between the presence of splenic macrophages and Intralipid administration.

Endocardial fibroelastosis and primary carnitine deficiency due to a defect in the plasma membrane carnitine transporter.

Endocardial fibroelastosis (EFE) has previously been shown to be associated with tissue carnitine deficiency, although the basis for the carnitine deficiency has not been documented. A patient with the classical features of EFE and marked deficiency of carnitine in heart muscle, skeletal muscle, and liver is presented in this report. Cultured skin fibroblasts from both parents demonstrated levels of carnitine uptake at 50% of the normal rate. This is consistent with heterozygosity for the plasma membrane carnitine transporter defect, indicating likely homozygosity for this recently recognized inborn error in the index patient.

Fractal geometric analysis of the renal arterial tree in infants and fetuses.

Fractal geometry is a useful method of quantitating the space-filling properties of complex objects and has a particular advantage in pediatric pathology because it is independent of organ size. The fractal dimensions of angiographic images of 44 renal arterial trees from 23 consent pediatric autopsies were measured by the box-counting method. The mean fractal dimension was 1.64 and all values were greater than the topological dimension (one), indicating that the renal arterial tree in fetuses and infants has a fractal element to its structure. There was no significant association with size of the kidneys, confirming the size-independent nature of the fractal dimension. There was no significant association with age of the subject, and the mean value was not significantly different from values obtained in studies of adult kidneys, suggesting that the degree of branching, at a lobar and lobular level, does not increase after about the 21st week of gestation. The results are compatible with a diffusion-limited aggregation model of development.

Are infantile myofibromatosis, congenital fibrosarcoma and congenital haemangiopericytoma histogenetically related?

Infantile myofibromatosis, congenital fibrosarcoma and congenital/infantile haemangiopericytoma are generally considered distinct entities. Overlapping microscopic features between infantile myofibromatosis and congenital fibrosarcoma, and between infantile myofibromatosis and congenital/infantile haemangiopericytoma, however, have been noted, but not formally reported. This report concerns six neonatal tumours, each exhibiting more than one of the above patterns, supporting a histogenetic relationship among these entities. Immunohistochemistry for smooth muscle actin was found to be useful in the diagnosis of congenital/infantile haemangiopericytoma, and also served to support a histogenetic relationship with the other two entities under consideration.

The anaphylaxis hypothesis of sudden infant death syndrome (SIDS): mast cell degranulation in cot death revealed by elevated concentrations of tryptase in serum.

A series of cases of sudden unexpected post-neonatal deaths from two centres in the UK have been investigated for evidence of mast cell activation using the biochemical markers tryptase and 9 alpha,11 beta-PGF2. Tryptase was selected as a possible marker because it is a component of mast cell secretory granules and, unlike histamine, it is not released from basophils. The prostaglandin 9 alpha,11 beta-PGF2 is an initial and pharmacologically active metabolite of PGD2, the major mast cell-derived cyclooxygenase product. This prostaglandin was chosen to serve as a marker of newly generated mediator release. In the study, unexplained infant deaths were associated with a higher concentration of tryptase in serum compared with cases of unexpected, but subsequently explained death. However, 9 alpha,11 beta-PGF2 was found to be an unsuitable post mortem marker in this situation. These results provide direct evidence that mast cell degranulation, possibly as a result of anaphylaxis, may be occurring around the time of death in some cases of cot death.

Age-related basement membrane thickening of the vocal cords in sudden infant death syndrome (SIDS).

Sudden infant death syndrome (SIDS) remains the leading cause of death in the Western world among infants between the ages of 1 month to 1 year. The diagnosis can only be established at autopsy, at which time no obvious or recognizable pathology is evident. A correlation between thickening of the basement membrane of the true vocal cords and the victim's age was observed in all 51 larynges examined, whereas no such finding was detected in 82 larynges of infants who died of other causes. Thus, the data support the authors' previous morphological results suggesting the use of basement membrane thickening as a marker of positive diagnosis of SIDS at autopsy. The possibility that an immune process may be associated with this syndrome merits further investigation and could prove to be of great importance.

Vitreous humour and cerebrospinal fluid hypoxanthine concentration as a marker of pre-mortem hypoxia in SIDS.

AIMS: To assess the rate at which premortem hypoxia occurs in sudden infant death syndrome (SIDS) when compared with death in early childhood. METHODS: The hypoxanthine concentration was measured as a marker of premortem hypoxia in vitreous humour and cerebrospinal fluid samples obtained at necropsy from 119 children whose ages ranged from 1 week to 2 years. RESULTS: Increasing interval between death and necropsy was accompanied by an increase in the hypoxanthine concentration of vitreous humour for the first 24 hours, at a rate of 8.3 mumol/l/hour. Thereafter, there was little change with time, and the results wer corrected to 24 hours according to a regression equation. Cerebrospinal fluid concentrations showed no significant change with time following death. Patients were divided into three groups according to the cause of death: SIDS, cardiac or pulmonary disease, and others. Median values for the cerebrospinal fluid hypoxanthine concentrations were not significantly different among the groups and no difference could be shown between the vitreous humour hypoxanthine concentration in cases of SIDS and those children dying from other causes. Patients with established cardiac or pulmonary disease had a significantly reduced vitreous humour hypoxanthine concentration which may have reflected the premortem use of artificial ventilation. CONCLUSIONS: The results of this study do not support the view that pre-mortem hypoxia is a common feature in SIDS when compared with other causes of death.