The role of post-mortem MRI in the neonatal intensive care unit.

OBJECTIVE: Post-mortem examination can provide important information about the cause of death and play a significant role in the bereavement process. Autopsies reveal previous unknown medical problems approximately 20 to 30% of the time. A non-invasive magnetic resonance imaging-based post-mortem examination (PM-MRI) may provide an alternative for families who do not consent to an autopsy. STUDY DESIGN: This study was a prospective observational study of recently expired neonates and infants. Subjects underwent a full body MRI scan (brain, chest, abdomen and pelvis) followed by conventional autopsy if the family desired to have one. MRI results were compared with autopsy findings and the ante-mortem clinical diagnosis. A follow-up survey was conducted to investigate family perceptions of the PM-MRI process. RESULTS: Thirty-one infants underwent full PM-MRI. Of 31 infants, 19 (61%) had complete agreement between the clinician's impression and PM-MRI. Twenty-four infants also had conventional autopsy, with 14/24 (58%) infants having PM-MRI results consistent with autopsy findings. PM-MRI was superior at detection of free intraperitoneal/intrathoracic air and hepatic iron overload. Whole-body PM-MRI did not have the resolution to detect focal/microscopic injury, vascular remodeling and some forms of brain injury. Of those families who remembered the PM-MRI findings, the majority felt that the information was useful. CONCLUSIONS: PM-MRI studies may provide an important adjunct to conventional autopsy and a substitute when the latter is not possible for personal or religious reasons. Clinicians should be aware of, and communicate with the family, the resolution limits of the whole-body PM-MRI to detect certain types of injury.

Respiratory failure in a term infant with cis and trans mutations in ABCA3.

A full-term female neonate presented with persistent respiratory failure and radiologic studies consistent with surfactant deficiency. Sequencing of the ATP-binding cassette transporter A3 gene (ABCA3) revealed three mutations: R280C, V1399M and Q1589X. The infant underwent bilateral lung transplantation at 9 months of age and is alive at 3 years of age. Parental sequencing demonstrated that two of the mutations (R280C and Q1589X) were oriented on the same allele (cis), whereas V1399M was oriented on the opposite allele (trans). As more than one mutation in ABCA3 can be present on the same allele, parental studies are needed to determine allelic orientation to inform clinical decision making and future reproductive counseling.

Paraneoplastic pemphigus and bronchiolitis obliterans associated with a mediastinal mass: A rare case of Castleman's disease with respiratory failure requiring lung transplantation.

Castleman's disease is an infrequent and usually benign lymphoproliferative disorder. Resection of the tumor usually is curative. The immunostimulatory nature of the tumor can, in rare instances, result in paraneoplastic manifestations. The authors present a case of a 14 year old with mucocutaneous ulcerations and progressive dyspnea that was found to have a large mediastinal mass and circulating autoantibodies that were responsible for his paraneoplastic pemphigus and bronchiolitis obliterans. In spite of aggressive immunotherapy to control the autoimmune mucocutaneous lesions, the pulmonary fibrosis was irreversible and progressed to pulmonary failure necessitating lung transplantation. J Pediatr Surg 36:E22.

Alveolar capillary dysplasia with misalignment of pulmonary veins and anterior segment dysgenesis of the eye: a report of a new association and review of the literature.

The association of alveolar capillary dysplasia with misalignment of pulmonary veins (ACD-MPV) and ocular abnormalities has not been previously reported. We present a case of ACD-MPV and anterior segment dysgenesis of the eye in a full-term infant as well as a review of the relevant literature.

Prolonged survival in hereditary surfactant protein B (SP-B) deficiency associated with a novel splicing mutation.

Hereditary surfactant protein B (SP-B) deficiency has been lethal in the first year of life without lung transplantation. We tested the hypothesis that SP-B gene mutations may result in milder phenotypes by investigating the mechanisms for lung disease in two children with less severe symptoms than have been previously observed in SP-B deficiency. Immunostaining patterns for pulmonary surfactant proteins were consistent with SP-B deficiency in both children. DNA sequence analysis indicated that both children were homozygous for a mutation in exon 5 that created an alternative splice site. Reverse transcriptase PCR and sequence analysis confirmed use of this splice site, which resulted in a frameshift and a premature termination codon in exon 7. The predominant reverse transcriptase PCR product, however, lacked exon 7, which restored the reading frame but would not allow translation of the exons that encode mature SP-B. Western blot analysis detected reduced amounts of mature SP-B as well as an aberrant SP-B proprotein that corresponded to the size expected from translation of the abnormal transcript. We conclude that a novel splicing mutation was the cause of lung disease in these children and that hereditary SP-B deficiency can be the cause of lung disease in older children.

Circumferential distribution of ganglion cells in the transition zone of children with Hirschsprung disease.

We prospectively studied the circumferential distribution of ganglion cells in the transition zone from a study population of 21 patients with Hirschsprung disease (HD) undergoing a pull-through procedure over a 26-month period. Twelve cases were satisfactory for examination, in that the transition zone was contained within a single surgical specimen and specimen distortion was minimal. Ganglion cells in the submucosa were counted in all 12 cases. In seven of the cases, the transition zone was proximal to the rectal sleeve and myenteric plexus ganglion cells were also counted. We found an uneven circumferential distribution of ganglion cells in both myenteric plexus and submucosa of the transition zone, resulting in a "leading edge" of ganglion cells extending into aganglionic distal bowel. The maximum length of this leading edge was 2.4 cm and 2.1 cm in the myenteric plexus and submucosa, respectively. Ganglion cells at the tip of the leading edge were present in clusters of up to six ganglion cells, in marked contrast to an absence of ganglion cells for most of the remainder of the circumference. Closely spaced myenteric plexus ganglia were seen at the tip of the leading edge in some cases. The leading edge was more frequently observed along the antimesenteric side, but this was not statistically significant. Our findings have relevance in the interpretation of intraoperative biopsies at the time of pull-through surgery and subsequent biopsies of neorectum in patients with surgically corrected HD.

Gliomatosis peritonei as a complication of a ventriculoperitoneal shunt: case report and review of the literature.

Gliomatosis peritonei, the implantation of neuroglial tissue upon the peritoneal surfaces, is a rare event most often associated with solid or immature teratomas of the ovary in young girls. The authors report a case of a 10-month-old girl with a ventriculoperitoneal shunt (VPS) who presented with bilateral inguinal hernias. Herniorrhaphy was uneventful. Microscopic examination of the hernia sacs showed exuberant mesothelial hyperplasia containing multiple nests of differentiated glial tissue. Subsequent computed tomography and laparoscopy disclosed normal ovaries with no evidence of intraabdominal or pelvic abnormalities. Gliomatosis peritonei in this case was attributed to transport of glial tissue from the cerebrospinal fluid into the peritoneal cavity via the shunt. With the exclusion of an ovarian germ cell neoplasm and in the presence of a VPS, the clinical course with regard to the glial implants in these children is uneventful. If it is appreciated that gliomatosis peritonei may be a complication of a VPS, an extensive clinical evaluation generally is unnecessary.

Bannayan-Riley-Ruvalcaba syndrome: spectrum of intestinal pathology including juvenile polyps.

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a disorder that includes juvenile polyposis as part of its pathologic spectrum, and it recently has been shown to share phenotypic and genotypic features with Cowden's disease. In existing literature, descriptions of intestinal pathology in patients with BRRS are relatively sparse and occasionally erroneous. We describe the intestinal pathology in multiple specimens from three children with BRRS. Examination of gastrointestinal biopsies from these children revealed predominantly colonic and rectal polyps with the histology of juvenile polyps. Additionally, two cases with clusters of ectopic ganglion cells within the lamina propria, one in a colonic polyp and one in a duodenal biopsy, and an atypical polyp were observed. Bannayan-Riley-Ruvalcaba syndrome should be included in the list of differential diagnostic considerations when a child or young adult presents with a juvenile polyp, particularly if unusual histologic features such as atypical polyps or ectopic ganglion cells are encountered.

Congenital disseminated malignant rhabdoid tumor: a distinct clinicopathologic entity demonstrating abnormalities of chromosome 22q11.

The clinical, pathologic, and immunohistochemical features of a widely disseminated tumor with rhabdoid phenotype are described in nine infants < or = 3 months of age. Five neonates had tumor evident at birth, two of which had placental metastases. The average survival following diagnosis was < 6 weeks. None of the infants had an apparent primary tumor in either the kidney or brain. In four cases, the dominant mass involved the head and neck region, and in two cases, the primary mass was paraspinal. The histologic features were those of a high-grade, round cell neoplasm with abundant cytoplasm and containing cells with cytoplasmic filamentous inclusions. Immunohistochemical studies revealed polyphenotypic antigen expression. Genetic information was available from eight of nine cases. Karyotype analysis revealed abnormalities of chromosome band 22q11-12 in three of six tumors. Fluorescence in situ hybridization studies or molecular studies demonstrated 22q11.2 deletions in all five cases with available frozen tissue, two of which had translocations involving 22q by karyotype analysis. The similar clinical and pathologic findings in these rapidly fatal tumors in infants and the demonstration of abnormalities of chromosome 22q11 in a majority of the cases supports their histogenetic and nosologic relationship to the family of malignant rhabdoid tumors that typically occur in young children in several anatomic sites, including kidney, soft tissues, liver, and brain. Like neuroblastoma and rhabdomyosarcoma, malignant rhabdoid tumor can appear as disseminated disease at birth or shortly thereafter.

Liver transplantation after jejunoileal bypass for morbid obesity.

BACKGROUND: Jejunoileal (JI) bypass was developed as a therapy for morbid obesity in the late 1960s but has since been abandoned because of a high rate of complications, including cirrhosis. The need for liver transplantation after JI bypass has been infrequent, with only four previous patients reported in the literature; however, because the time to develop symptomatic end-stage liver disease after JI bypass may be quite long (25 years or more), the incidence of patients who will require liver transplantation may only now be increasing. STUDY DESIGN: We reviewed our experience with JI bypass and liver transplantation in 380 consecutive adult patients since 1985. RESULTS: Four patients underwent liver transplantation for cirrhosis after JI bypass, all within the last 48 months. The mean duration of time from JI bypass to transplantation was 22.3 years. All patients had complications, in addition to their liver disease, which were related to the JI bypass, which included nephrolithiasis, cholelithiasis, vitamin deficiencies, renal insufficiency, and d-lactic acidosis. One patient had the JI bypass taken down before transplantation, which precipitated acute liver and renal failure, necessitating urgent transplantation. One patient, who had the JI bypass taken down at the time of transplant, has developed recurrent morbid obesity, while the other three patients have not. The one patient who has not had the JI bypass taken down has not developed evidence of recurrent liver disease and is followed with monthly liver function tests and yearly biopsies. CONCLUSIONS: The incidence of patients who require liver transplantation after JI bypass may be on the increase. Take down of the JI bypass may precipitate acute liver failure in the cirrhotic patient. JI bypass should be accomplished either at the time of transplantation or if signs of liver dysfunction occur after transplantation. Liver transplant recipients can be at risk for recurrent obesity after takedown of the JI bypass. Transplantation for those patients with decompensated cirrhosis after JI bypass has demonstrated excellent early results.

Pathologic features of rhabdomyosarcoma before and after treatment: a clinicopathologic and immunohistochemical analysis.

Few studies have analyzed the relationship among pathology, therapy-induced changes, proliferative activity, and outcome for rhabdomyosarcoma (RMS), despite the challenges of histopathologic interpretation of this tumor after treatment. Although cytodifferentiation and decreased mitotic activity after treatment were documented previously, the clinical consequences of these changes are uncertain because of the small number of cases analyzed. We analyzed 16 RMSs with pre- and post-treatment specimens for clinicopathologic features, outcome, and immunohistochemical data on formalin-fixed, paraffin-embedded tissue for vimentin, smooth muscle actin, muscle-specific actin, desmin, myoglobin, p53 protein, topoisomerase II-alpha, and MIB-1 proliferative activity. Four of eight alveolar (ARMS), five of five botryoid (BRMS), and two of three nonbotryoid embryonal (ERMS) RMSs displayed varying degrees of post-therapeutic histologic maturation and expressed one or more myoid markers. The remaining five RMSs had no cytodifferentiation. Myoid marker expression did not change significantly. In BRMS, MIB-1 and topoisomerase II-alpha proliferative activity decreased after therapy and correlated with cytodifferentiation and survival. This relationship was less clear for ERMS and ARMS. Five nonbotryoid RMSs without cytodifferentiation had either unchanged or increased proliferative activity, and four of these patients died of RMS. Six nonbotryoid RMSs with both cytodifferentiation and residual foci of undifferentiated cells had variable outcomes, including longer survival. We conclude that BRMS and ERMS exhibit therapy-induced cytodifferentiation more frequently than does ARMS. Cytodifferentiation and decreased proliferative activity are associated with favorable outcome in BRMS; unchanged or increased post-therapeutic proliferative activity suggests aggressive biologic potential in ERMS and ARMS. Combined patterns of cytodifferentiation and residual undifferentiated foci might be associated with increased, decreased, or unchanged proliferative activity and are difficult to interpret, but the presence of cytodifferentiation might presage an improved survival. Immunohistochemical analysis for proliferation markers might be useful for highlighting foci of less differentiated RMS or cytodifferentiated tumor cells in contrast to non-neoplastic, terminally differentiated muscle cells.

Nonrandom chromosomal gains in pilocytic astrocytomas of childhood.

Low-grade astrocytomas are the most common central nervous system (CNS) tumor occurring in the pediatric age group. Although many of these tumors are karyotypically normal, various studies have reported gains of chromosomes in a significant proportion of cases. We have the opportunity to karyotype two pilocytic astrocytomas occurring in 5- and 15-year-old children. These tumors were characterized by stemlines of 49,XY,+4,+7,+8 and 48,XX,+7,+8. Using these patients as index cases and based on additional karyotypic data that have been published, we performed fluorescence in situ hybridization on 25 additional cases of low-grade astrocytomas in children using pericentromeric probes for chromosomes 4, 6, 7, 8, 9, 10, 11, 12, 15, and 17. Six of 18 (excluding the two index cases), or one third, of the pilocytic astrocytomas were characterized by chromosomal gains, most commonly chromosomes 7 and 8, suggesting that trisomy 7 and 8 are relatively common events in the tumorigenesis of pilocytic astrocytomas. In contrast, chromosomal trisomies were not detected in seven well-differentiated fibrillary astrocytomas with any of the probes chosen.

Pathology of intestinal transplantation in children.

The role of mucosal biopsy in the monitoring of pediatric intestinal allografts is analyzed. We performed a retrospective review of all biopsy, resection, and autopsy material from 22 bowel allografts in 21 patients, followed from 6 months to 3 1/4 years and treated on an immuno-suppressive regimen based on FK 506 (Tacrolimus). There were 579 biopsies, of which 35 were stomal, with two to three fragments taken at each biopsy. There were three explanted bowels and three autopsies. Stomal biopsies proved to be inappropriate for monitoring. Biopsies with three to five pieces of tissue per site, under endoscopic direction, provided the most information. Early cellular infiltrate with lymphoid activation in the absence of epithelial apoptotic figures was not considered sufficient to diagnose rejection although preceded it in most instances. At least two apoptotic figures in a gland or several single apoptotic cells in the presence of a lymphoid infiltrate with activated lymphoid follicles and prominent endothelium correlate best with clinical rejection and response to antirejection measures. Epstein-Barr viral disease is common in this population, and early, late, and noncontiguous bowel involvement can be subtle and difficult to distinguish from rejection, though without the apoptosis. Epstein-Barr virus in situ probes are essential to make the differential diagnosis and the two conditions may co-exist. Mucosal biopsy monitoring appears to be of clinical utility and is part of a program that involves clinical, endoscopic, microbiological, and morphologic assessment.

Fetal parvovirus B19 infection and liver disease of antenatal onset in an infant with Ebstein's anomaly.

Fetal parvovirus B19 infection has been reported in association with hydrops and fetal demise, myocarditis, and congenital anomalies, as well as with normal outcome of pregnancy. One infant with liver disease of fetal onset associated with parvovirus B19 infection has been described. We have seen another such infant, in whom marked siderosis of the liver suggested accelerated destruction of erythrocytes and portal tract fibrosis with proliferation of bile ducts suggested intrauterine infection. Viral cytopathic effects were not seen. Maternal serum obtained postpartum contained IgM class antibodies against parvovirus B19, and parvovirus B19 nucleic acid sequences were identified in the infant's liver by polymerase chain reaction studies. We propose that recognition of this combination of siderosis with fibrosis and bile duct proliferation will permit identification of cases of fetal parvovirus B19 infection.

A syndrome involving immunodeficiency and multiple intestinal atresias.

Multiple intestinal atresias (MIA) is a severe form of intestinal atresias throughout the gastrointestinal tract. In two reports, MIA have been associated with severe immunodeficiency. We report a newborn girl who had profound humoral and B cell immunodeficiency and impaired T cell function. The patient had agammaglobulinemia and decreased blood lymphocytes, with virtually no B cells in the blood or in intestinal lymph nodes. T cells were reduced in number and weakly proliferated to mitogens. These data suggest that a syndrome involving the development of MIA is associated with various forms of severe immunodeficiency, and therefore newborns with MIA should be examined for immunodeficiency.

Occult breast calcifications sampled with large-core biopsy: confirmation with radiography of the specimen.

In a series of nine stereotaxic large-core biopsies of calcifications, radiography of the specimen was used to ensure that appropriate tissue was removed. In eight cases, calcifications were evident at radiography as well as at histologic evaluation. Four cases were malignant and four were benign, and in one case in which calcification was not evident at either radiographic or histologic evaluation, a benign process was confirmed at surgical excision. Radiography of the specimen is a key component in diagnosis of breast calcifications sampled with large-core technique.

Lipid metabolism during early stages of Wallerian degeneration in the rat sciatic nerve.

We examined changes in biosynthetic capacity of sciatic nerve during the early stages of Wallerian degeneration, utilizing a model that permits exclusion of nonresident cells from degenerating nerve. Sciatic nerve segments were placed in either 5-microns pore (allowing infiltration of nonresident cells) or 0.22-microns pore (excluding nonresident cells) Millipore diffusion chambers and then implanted in the peritoneal cavity of the same 32-34-day-old rat. At times up to 7 days postsurgery, nerve segments from the chambers, as well as control segments from the contralateral sciatic nerve, were removed and their capacity to incorporate radioactive precursors into lipids and proteins assayed in vitro. In nerve segments from both the 0.22- and 5-microns pore chambers, incorporation of [14C]acetate into total lipids was decreased relative to control by 50% at 12 h postsurgery and by 85% at day 3. This decreased incorporation of [14C]acetate reflects primarily decreased de novo synthesis of cholesterol and of fatty acyl residues incorporated into glycerolipids and sphingolipids. There was a preferentially decreased synthesis of cerebrosides and cholesterol (components enriched in myelin) relative to other lipids, while cholesterol esters and free fatty acids (products of membrane degradation) accounted for a greater proportion of the greatly reduced levels of total lipid label. In contrast to [14C]acetate, incorporation of [3H]glycerol into lipids was increased up to fourfold, relative to control, 1 day after nerve transection.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolism of functional groups modifying the CNS myelin-associated glycoprotein.

We have examined the metabolic turnover of the peptide backbone of the CNS myelin-associated glycoprotein (MAG) and of the fucose and sulfate groups modifying this protein. Rats (20 or 90 days old) were injected intracranially with mixtures of [3H]fucose and [14C]glycine, [3H]glycine and [35S]sulfuric acid, or [3H]fucose and [35S]sulfuric acid. At times ranging from 30 min to 4 weeks later, myelin was isolated, and radioactivity in MAG was determined following electrophoretic separation. Following the peak of incorporation, glycine-derived radioactivity in the MAG peptide backbone declined several-fold during the first week and was then metabolically stable (half-life much greater than 1 month). Declines with time in [3H]fucose- and [35S]sulfate-derived radioactivity in MAG were similar to that of [3H]glycine, an observation indicating that the fucose and sulfate groups modifying MAG are metabolized together with the peptide backbone as a single metabolic entity. These results were confirmed by experiments involving selective immunoprecipitation of MAG. The rates of incorporation of labeled glycine, fucose, and sulfate into MAG all decreased approximately 12-fold between 20 days of age and adulthood, a finding providing further evidence for concerted turnover of the entire molecule. Because of this concerted turnover, we suggest that functional groups modifying MAG serve some permanent structural role in protein configuration.

Expression of myelin components in mouse Schwann cells in culture.

Mouse Schwann cells cultured in vitro are capable of expressing basal levels of the major myelin components P1, P2, P0, and galactocerebroside. Numerical counts of immunostained cultures indicated that between 22 and 40% of the cells are positive up to 21 days for all of the components indicated. Electrophoretic analysis of Schwann cells labeled with a 14C-amino acid mixture revealed the presence of proteins with relative mobilities identical to those of P0 and P1. Positive identification of the two proteins was indicated by immunoprecipitation of P1 and immunoblotting of P0. These data show that in the absence of neurites, Schwann cells in culture can express low levels of myelin characteristic components even in the absence of myelin assembly.