A13-year-old male child presented with headache and vomiting of one-month duration.There was horizontal nystagmus, and fundus examination revealedbilateral papilloidema. There was no motor or sensory de¢cit. Contrast enhanced computed tomographs of the cranium (F|gure 1) revealed an inhomogenous poorly enhancing mass involving the fourth ventricle with gross obstructive hydrocephalus. A suboccipital craniectomy and near total excision of the tumor was done. The tumor was ¢lling the fourth ventricle and extending down to the third cervical vertebra. Microscopically, the tumor consisted of large polygonal cells arranged in sheets, occasionally showing a perivascular orientatation. A large number of tumor cells contained aprominent, ¢nely dispersed granular brownpigment (F|gure 2). These granules acquired a deep green color on Schmorl’s stain (F|gure 3). The pigment was Prussian blue negative, PAS positive (F|gure 4), and bleached by potassium permanganate treatment. Tumor cells did not express HMB-45.
Bone biopsies were performed before and 7 weeks after transplantation of HLA-compatible bone marrow from the sister of a 3-month-old male infant with malignant autosomal recessive osteopetrosis due to a mutation in the TCIRG1 (ATP6i) gene. The first biopsy showed broad, immature bony trabeculae and no medullary hematopoiesis. Only few osteoclasts were present and electron microscopy showed absence of ruffled borders. The post transplant biopsy revealed donor osteoclasts with ruffled borders and intracytoplasmic mineral crystals as proof of active bone resorption that had not yet been detectable radiographically. Osteopetrosis is a genetically heterogeneous disease. Definition at the DNA-level will enable comparison of treatment strategies and prenatal diagnosis. As shown in this patient, the autosomal recessive form caused by a TCIRG1 gene mutation may be amenable to bone marrow transplantation. Activity of donor osteoclasts can be demonstrated morphologically on biopsy, before bone remodeling becomes evident radiologically.
Bone mineral density is a quantitative trait influenced by both genetic and environmental factors. Epidemiological and twin studies have shown heritability for the variance of bone density of up to 80%. The role of genetic factors in bone homeostasis also is clearly illustrated by the existence of an extended group of genetic conditions associated with an abnormal bone density. These conditions are mainly monogenic in that they are caused by mutations in one gene. Recent developments in molecular genetics and genomics have resulted in a dramatically increased power to identify such disease-causing genes. The group of conditions with increased bone density has been poorly studied and understood at the molecular genetic level but recently for some of them, major breakthroughs have been made. These findings will make the molecular analysis of such patients an additional tool in diagnostics and in genetic counseling.
Deletion 22q11.2 is a chromosomal abnormality detected in young patients with clinical manifestations of the DiGeorge/velocardiofacial syndrome. Conotruncal heart defects are also associated with del22q11.2. An association of these cardiac malformations with neoplasias has been observed. Our series includes two cases of malignancies, a hepatoblastoma and a renal-cell carcinoma, arising in children with complex cardiac malformations. The aim of the study was to determine if the deletion at 22q11.2 was present and could be responsible for both pathological processes. Del22q11.2 was identified in both cases. Comparative genomic hybridization revealed terminal gains on chromosomes 1q and Xq and terminal loss on 1p in the hepatoblastoma, and gains in 1p, 12q, 16p, 20q, 22q, and whole chromosome 19 and loss of Xq in the renal-cell carcinoma. Our results confirm a common genetic basis for cardiac malformations, and del22q11.2 presents a risk factor for the development of pediatric tumours.
We have used semiquantitative comparative and real-time quantitative polymerase chain reactions (PCR) to detect n-myc gene-amplification in 20 frozen neuroblastoma biopsies and IMR 32 cell line to predict biological behavior of the tumors. Two primer pairs were used for the semiquantitative method to co-amplify a 520-bp fragment of the beta-globin gene--used as a single copy reference standard--and a 258-bp fragment of the n-myc gene. After 30 cycles the PCR products were electrophoresed through an agarose gel and were compared to each other with use of a gel-densitometer. Real-time quantitative analyses were performed in a LightCycler instrument. A single primer pair was used to amplify a 120-bp fragment of the n-myc oncogene and a LC640-labeled fluorescent probe pair to detect the product. Calibration curve, set up from a serial dilution including samples with 1, 2, 10, 13, 25-fold n-myc oncogene amplification, was used for quantitative analysis. The semiquantitative method did not show distinct difference between tumor groups with no amplification and less than 10-fold amplification, whereas quantitative LightCycler analysis was able to detect even 2-fold amplification. Differentiated neuroblastomas seldom show n-myc amplification. In spite of this, we have found two partly differentiated tumor samples that contained n-myc amplification. In these cases in situ PCRs were performed to examine the tumor heterogeneity. We used biotinated ATP labeling and the same primer pair as for the LightCycler analysis. In both cases differentiated cells did not show n-myc gene amplification, whereas considerable amplification was detected in the neuroblasts.
Jorge Lujan-Zilbermann u Assistant Professor of Pediatrics, University of South Florida College ofMedicine,Tampa, Florida, USA Atilano Lacson u Clinical Associate Professor of Pediatrics, University of South Florida College ofMedicine and Pediatric Pathologist, All Children’s Hospital, St. Petersburg, Florida, USA Enid Gilbert-Barness u Professor of Pathology and LaboratoryMedicine, Pediatrics, and Obstetrics and Gynecology, University of South Florida College ofMedicine,Tampa, Florida, USA Herbert H. Pomerance u Professor of Pediatrics, University of South Florida College of Medicine,Tampa, Florida, USA
A2790-gs full-termmalebornby normal spontaneous vaginal delivery to a 28year-old gravida 2 para1with antenatal fetal diagnosis of cystic left lungmass associated with mediastinal shift to the right and no hydrops fetalis. The lung mass was ¢rst seen at 20 weeks gestation on ultrasound and increased in size over 9 weeks. Follow-up ultrasound at 34 weeks showed decrease in size of the mass. Karytotypewas 46XY. Apgar scores were 9 and 9 at1and 5 min, respectively. Physical examination of the infant at birth revealed tachypneawith respiratory rate 80=min min and mild lower intercostal retractions. Air entry was equal and good bilaterally. Heart soundswere heardbest to the right of themidline.Oxygen saturation remained 96^99%. Initial blood gas was within normal limits. Baby was placed on nasal CPAP 4 with F|02 0.25 due to increasing tachypnea anddesaturation. ChestX-ray showed left lower lobe density, withmediastinal shift to the right. Left diaphragmwasvisualizedwell (F|gure1).Computedtomography (CT) scanwith POcontrast con¢rmedthe cystic left lungmass (F|gure 2). Di¡erential diagnosis included bronchopulmonary sequestration and congenital cystic adenomatoid (CCAM) malformation of the lung.The baby had increased pCO2 with tachypnea needing intubation and mechanical ventilation from the 5th day. Echocardiogram showed tiny patent ductus arteriosus (PDA), large left atrial appendage, and a large £ow in left pulmonary veins.Thebabyhadelective surgeryonthe11th day. At surgery, amassmeasuring 5 4 cmwas removedandcon¢rmedtobe a left extralobar sequestrationwithblood supply fromavessel arising fromthe aorta.Thebabywas extubated uneventfully on the 3rd postoperative day and placed on nasal CPAP for1day before weaning o¡ to room air.The infant remained tachypneic intermittently with respiratory rate up to 80=min for 2 days.The baby was discharged on the10th postoperative day in stable condition.Histopathologyof themass con¢rmedthe diagnosis (F|gure 3).
Sialyl-Tn antigen (STn) is a mucin-type carbohydrate normally present in goblet cells of small and large bowel. STn expression has been demonstrated to occur in complete and incomplete intestinal metaplasia as well as in many carcinomas but in no normal gastric cell. The aim of our present study was to evaluate the distribution of STn in Helicobacter pylori chronic gastritis (HpCG) of pediatric patients. Eighteen gastric biopsies from 15 children (mean age: 11.5 years) with HpCG, 9 gastric biopsies from 9 children without H. pylori infection, and 1 heterotopic gastric mucosa in Meckel's diverticulum were immunostained using the anti-STn antibody STn1 (18/18), NCL-MUC-1 (7/18), and NCL-MUC-2 (18/18) antibodies. Also, sulfated mucosubstances were investigated with the Alcian Blue-Periodic Acid Schiff (AB-PAS), pH 1.0 stain. Although with different intensity (weak in 5/18, moderate 9/18, and intense 4/18) all cases with HpCG exhibited STn immunoreactivity. The expression of STn was found to be located mainly to the supranuclear region of the epithelial cells at the foveolae and glandular necks, with occasional cells showing diffuse cytoplasmic staining. When reactivity was intense, it was for the most part found in the cells at the neck of the glands. The mucus out of the luminal border above the positive cells was usually also stained. MUC-1 was negative (2/7) or weakly positive (5/7) in a few surface mucous cells. MUC-2 was negative (16/18) or occasionally detected in some foveolar and surface cells (2/18). AB-PAS pH 1.0 revealed the presence of sulfomucins in the cytoplasm of isolated cells of gastric pits and glands of most cases (11/15). None of these findings was observed in the control group. We conclude that STn can be identified in gastric cells of pediatric patients with HpCG and that this does not correlate with other mucosubtances markers. The findings could indicate that minimal intestinal metaplasia takes place in children with HpCG.
Campomelic dysplasia (CD, MIM 114290) is characterised by widespread osseous abnormalities including bowing of the long bones, dysplasia of the cartilage of the tracheobronchial tree, and neurological abnormalities leading to high perinatal lethality. A majority of karyotypic males present as phenotypic females. The disorder has only recently been categorised as a dominantly transmitted entity after demonstration of heterozygous mutations in the SOX9 gene on chromosome 17q24.3 or translocations associated with breakpoints upstream of this gene. Despite this mode of transmission, only two well-documented instances of parent-child transmission of the disorder have been described. We report a man of normal intelligence with mild phenotypic and radiological appearances of CD. His first-born child, a phenotypic female with a 46,XY karyotype, presented with significantly more severe skeletal and neurological involvement. Parents of individuals with CD should be examined for minimal manifestations of the disorder, which may represent phenotypic variability in the syndrome or somatic mosaicism.
(2003). PATHOLOGY TEACH AND TELL: NASOPHARYNGEAL ANGIOFIBROMA. Pediatric Pathology & Molecular Medicine: Vol. 22, No. 4, pp. 363-367.
The isoprenoid pathway produces three key metabolites: endogenous digoxin (regulator of neurotransmitter uptake), dolichol, and ubiquinone (free radical scavenger). Because a mitochondrial dysfunction has been described in Reye's syndrome, we thought it pertinent to assess the pathway in this disease. Since endogenous digoxin can regulate neurotransmitter transport, the pathway also was assessed in patients with right hemispheric, left hemispheric, and bihemispheric dominance to find out the role of hemispheric dominance in its pathogenesis. The plasma/serum activity of HMG CoA reductase, magnesium, digoxin, dolichol, ubiquinone, tryptophan/tyrosine catabolic patterns, free radical, and lipid levels aswellas (red blood cell) RBC Na+-K(+)ATPase activity were measured in the above mentioned groups. Results: In the patient group as well as in individuals with right hemispheric dominance similar patterns were obtained. There was elevated digoxin and dolichol levels with low levels of ubiquinone in patients with Reye's syndrome as well as in those with right hemispheric dominance. The serum magnesium and RBC Na+ -K(+)ATPase activity were reduced. There also was an increase in tryptophan catabolites and a reduction in tyrosine catabolites as well as increased free radical levels. Reye's syndrome is associated with an upregulated isoprenoid pathway, elevated hypothalamic digoxin secretion, and right hemispheric chemical dominance.
A10-year-old female child presentedwith history of o¡-and-on abdominal pain present for 2 years. The pain had become more frequent and colicky in the last 15 days. It was present in the hypogastrium and periumbilical area.There was history of constipation and an occasional episode of fresh blood with stools. She was the secondof twins and the other twin sister was asymptomatic. On examination,melanosis was seen on the lips, oral mucosa, and tips of ¢ngers and toes since 1 year of age. Her mother had similar symptoms at 15 years of age for which she underwent an abdominal surgery. A part of the small bowel was resected and it was said to be studded with a few polyps. No written document or histopathology report is available. The mother has been asymptomatic ever since.The mother and the younger brotheralsohadoralmelanosis.Thebrother, however, hasbeenasymptomatic so far. On examination of the index case there was amass present in the periumbilical area measuring 5 3 cm. Reducible intussusception was present. Resection of the small intestine at two places was done with end-to-end anastomosis.Two segments (18 cm each) of the small intestine were resected, 9 inches from the duodenojejunal junction and at the jejunoilial junction. Both segments of the small intestine contained two polyps each.The largest polyp (5 cm in diameter) was seen 9 cm distal to the duodenojejunal junction, was pedunculated, and there were small cysts with mucoid material present at all levels of the wall including the serosa (Figure 1). The other three polyps were sessile and ranged from 2 to 4 cm in diameter. They too showed small cystic spaces with mucoid material. Microscopically the polyps revealed a classic morphology. Normal smallintestinal glands rested on a branching smooth muscle framework (Figure 2). There was no evidence of dysplasia. Transmural herniation of the mucosal glands admixed with smooth muscle ¢bers and lamina propria was seen until the serosa (Figure 3). Apart from this there were cystically dilated spaces (0.2^1 cm diameter)
The diagnosis of congenital nephrotic syndrome (NS) is a challenge both for clinicians and for pathologists. We observed three cases in a series of 50 children with NS nonresponsive to therapy, corresponding to one case each of minimal change disease, Finnish-type glomerulopathy, and diffuse mesangial sclerosis--two histopathologic studies were performed in each case. The age at presentation did not predict the diagnosis nor the prognosis: The NS presented at 7 months of age in the patient with diffuse mesangial sclerosis, but it was present at birth in the patient with minimal change disease. In these 2 patients the final diagnosis was made with the first renal biopsy. Conversely, in the patient with Finnish-type glomerulopathy, the diagnosis was only possible in the repeat biopsy, as the early pathologic changes were nonspecific. This study shows the essential role of the renal biopsy in determining the etiologic diagnosis and prognosis in patients with congenital nephrotic syndrome.
Atypical teratoid/rhabdoid tumor (AT/RT) is extremely malignant, highly aggressive primitive central nervous systemneoplasm of infancy with very poor prognosis. Histologically, AT/RT is defined as a polymorphous neoplasm often featuring rhabdoid, PNET, mesenchymal, and epithelial components. We report the clinical history, radioligical, and pathological findings in a child affected bycentral nervous system AT/RT.
Rosai-Dorfman disease (RDD) is a rare histiocytic proliferative disorder with massive lymphadenopathy. We here describe RDD of a neonate who presented with paleness and hepatosplenomegaly but not lymph-node swelling. Routine laboratory studies showed anemia, thrombocytopenia, and an elevated value of gamma-glutamyl transpeptidase. Histological examination of the liver revealed a proliferation of histiocytes with abundant eosinophilic cytoplasm, which were positive for S-100 protein and CD68 but not CD1a and did not reveal Birbeck granules. Radiological studies showed hepatosplenomegaly and a narrowing of the hepatic vein, which might have contributed to hypersplenism resulting in anemia and thrombocytopenia. This case is thought to be congenital RDD without lymphadenopathy.
Yolk sac tumor (YST) of prepubertal testis is a peculiar neoplasm with overall good prognosis. There are no known conditions associated with the development of this tumor. The case of a 2-year-old boy with testicular YST and presence of testicular microlithiasis (TM) in the adjacent-still-recognizable testicular tissue is reported. Concentrically laminated microliths were clearly extratubular structures. Ultrasound of the remaining testis revealed microlithiasis. Bilateral TM is being recognized with increasing frequency due to the extensive use of ultrasound. The exact meaning of its finding has not been definitively elucidated, but the association of TM with cryptorchidism, intratubular germ cell neoplasia and germ cell tumors either of the testis or mediastinum is on record. The combination of prepubertal YST and bilateral TM has not been reported previously. Finding of TM at this early age suggests a congenital deranged Sertoli cell function and/or an abnormal gonadal embryogenesis in its pathogenesis.
To find out if Cantrell's pentad is a single entity, four cases of ectopia cordis were studied and compared with cases in the literature. Our cases had the heart outside the thorax and had two to four other features of the association. In one case the thoracic organs had apparently escaped through a diaphragmatic hernia into an omphalocele, and in the others via a thoracoschisis with an abdominal defect, either a supraumbilical hernia or a gastroschisis. According to these cases and those from the literature, it is proposed that there are two major mechanisms leading to ectopia cordis: (1) a reversed diaphragmatic hernia in the case of a large diaphragmatic defect and an omphalocele, and (2) through a sterno-costal defect, with gastroschisis or a supraumbililical abdominal defect. As omphaloceles and major diaphragmatic defects are probably pathogenetically distinct from thoraco- and thoracogastroschisis, it is important to distinguish these groups of anomalies, rather than be concerned as to their relationship with Cantrell's pentad.
The psoralens are naturally occurring secondary metabolites in plants, including many fruits and vegetables. Health risks have been associated with handling or ingesting psoralen-containing plants, and with the use of synthetic psoralens in photochemotherapy of skin disorders. Our research has demonstrated that administration of the psoralens bergapten (5-methoxypsoralen) and xanthotoxin (8-methoxypsoralen) in the diet of female rats reduced birthrates, number of implantation sites, pups, corpora lutea, full and empty uterine weight, and circulating estrogen levels in a dose-dependent manner. Psoralens induced mRNAs of the liver enzymes CYP1A1 and UGT1A6, suggesting that enhanced metabolism of estrogens by psoralen treatment may explain the reproductive toxicity and the observed reduction of ovarian follicular function and ovulation. Rats also avoided repeated consumption of a flavored solution associated with psoralen administration. The findings indicate that the psoralens constitute a novel group of ovarian toxicants. Further examination of the safety of their use in photochemotherapy and diet is warranted.
Ornithine transcarbamylase deficiency, an X-linked disorder, is the most common inherited urea cycle defect. Previous reports have documented the existence of several different mutations that can, partly at least, explain the phenotypic variability of the disorder. We describe the only male with T343K mutation, which also is present in his mother. We underline the disorientation of the beginning of clinical presentation; the patient became ill when fruits were added to his diet.
Mutations in a sulfate-chloride antiporter gene, the diastrophic dysplasia sulfate transporter (DTDST), have been associated with a family of skeletal dysplasias including recessive multiple epiphyseal dysplasia, diastrophic dysplasia (DTD), atelosteogenesis type 2, and achondrogenesis type 1B (ACG1B). DTDST function is crucial for uptake of extracellular sulfate required for proteoglycan (PG) sulfation; the tissue-specific expression of the clinical phenotype may be the consequence of the high rate of PG synthesis in chondrocytes and the ensuing high sulfate requirement. We have studied the contribution of cysteine and its derivatives to PG sulfation in fibroblast and chondrocyte cultures from sulfate transporter dysplasia patients. Incubation of ACG1B fibroblasts in medium containing different concentrations of cystine indicated partial recovery of PG sulfation as measured by HPLC disaccharide analysis of chondroitin sulfate PGs; similar results were observed after incubation with N-acetylcysteine. When both compounds were tested in primary chondrocytes from a DTD patient, partial rescue of PG sulfation was observed, suggesting that the metabolic pathways producing cytoplasmic sulfate from thiols are also active in this cell type.
