Primary Spinal Epidural/Extramedullary Ewing Sarcoma in Young Female Patients.

Primary spinal epidural/extramedullary ewing sarcoma (ES) is a rare extraosseous lesion. Extraosseous ES has a similar demographic as osseous ES, primarily affecting adolescents and young adults and male propensity. Reported 5-year survival is 0% to 37.5% for spinal extraosseous ES. METHODS: Two girls, 19 and 14 months old, presented with progressive lower extremity paraplegia and incontinence. Both had a compressive epidural/extramedullary mass without metastases and underwent decompression with multilevel laminectomy and tumor excision. Primary spinal epidural/extramedullary ES was diagnosed. RESULTS: Case 1 received 34 weeks of chemotherapy and radiation therapy, and case 2 received 14 cycles of chemotherapy and autologous stem cell rescue without radiation therapy. After more than 5- and 8-year follow-up, case 1 and case 2 are walking and disease-free, respectively. CONCLUSION: These cases are the youngest presentation reported for primary spinal epidural/extramedullary ES and suggest that toddlers have a better prognosis for survival than older children and adolescents.

Clinical and molecular characterization of novel deletions causing epsilon gamma delta beta thalassemia: Report of two cases.

Epsilon gamma delta beta (εγδß)0 - thalassemia is a very rare disorder that results from large deletions in the ß-globin gene cluster which abolish all regional globin chain gene expression from that allele. Since it is an exceedingly rare cause of neonatal anemia and is not detected by routine newborn screening, it is usually not suspected clinically and commonly undiagnosed or misdiagnosed. In this study, we describe two patients diagnosed in our hospital with (εγδß)0-thalassemia based on the results obtained from DNA microarray analysis of their peripheral blood. The first patient of mixed European descent presented as a neonate with microcytic hemolytic anemia, hyperbilirubinemia, hypoglycemia and hypothermia, and was found to have a 2.2 Mb loss that included the entire ß-globin gene cluster and the locus control region (LCR). The second patient, also of mixed European descent, presented in the neonatal period with anemia, thrombocytopenia and cutaneous extramedullary hematopoiesis, and was found to have a 59 kb loss that included the ß-globin LCR, HBE1, HBG1, and HBG2 genes. Both cases highlight the importance of recognizing the clinical features of (εγδß)0-thalassemia and implementing appropriate testing to clarify the diagnosis and manage the condition.

Dysgerminoma in a 10-Year Old with 45X/46XY Turner Syndrome Mosaicism.

BACKGROUND: Turner syndrome is a genetic disorder resulting from the absence of or structural abnormality of one X chromosome. The presence of Y chromosome material in girls with Turner syndrome confers an increased risk of benign and malignant germ cell tumor and prophylactic bilateral gonadectomy is recommended. CASE: A 10-year-old Turner mosaic syndrome (45X/46XY) patient underwent prophylactic gonadectomy after unremarkable preoperative pelvic imaging. Histopathology showed a streak right gonad, and left gonad with gonadoblastoma with limited degree of infiltrating germinoma. SUMMARYAND CONCLUSION: Gonadoblastoma and dysgerminoma have been reported in girls with Turner mosaic who carry Y chromosome material. Prophylactic gonadectomy should be considered in these girls without delay.

Neuroblastoma in Adolescents and Children Older than 10 Years: Unusual Clinicopathologic and Biologic Features.

Neuroblastoma (NB) in children older than 10 years is rare. We reviewed our archives for patients with NB aged 10 to 18 years and summarized their clinicopathologic/genetic records. Of 96 patients, 4 patients were identified in this age group. Four tumors were abdominal; 1 patient had 2 tumors at diagnosis, one of which was presacral. Tumor sizes ranged from 3 to 20 cm. All tumors were high risk at clinical stages 3 and 4, with metastasis to bone marrow and other areas. Four tumors were poorly differentiated with unfavorable histology and one patient with bilateral adrenal disease had an intermixed ganglioneuroblastoma on one side. Another tumor exhibited pheochromocytoma-like morphology. MYCN amplification was present in bone marrow metastasis in one case. Complex chromosomal gains and 19p deletions were common. Exome sequencing revealed ALK variants in 2 cases and previously unreported MAGI2, RUNX1, and MLL mutations. All patients received standard chemotherapy and 2 patients received ALK-targeted trial therapy. Three patients died of disease, ranging 18 to 23 months after diagnosis. One patient has active disease and is receiving trial therapy. In conclusion, NB in children older than 10 years may exhibit unusual clinicopathologic and genetic features with large tumors, bilateral adrenal disease, rare morphologic features, complex DNA microarray findings and novel mutations. Patients often have grim prognoses despite genomic profiling-guided targeted therapy.

Endobronchial Glomus Tumor in a Child.

Glomus tumors (GTs) are rare, usually benign, mesenchymal neoplasms typically located in the cutaneous tissues of the extremities. Visceral locations have been reported in ∼5% of cases. The average age at diagnosis is 42 years. GTs originating in the respiratory tract of pediatric patients are exceedingly rare. We report a 16-year-old male with a GT of the right lower lobe bronchus.

Arthrogryposis and pterygia as lethal end manifestations of genetically defined congenital myopathies.

Arthrogryposis multiplex congenita affects approximately 1 in 3,000 individuals of different ethnic backgrounds and displays an equal incidence in males and females. The underlying mechanism for congenital contracture of the joints is decreased fetal movement during intrauterine development. This disorder is associated with over 400 medical conditions and 350 known genes that display considerable variability in phenotypic expression. In this report, four fetal or perinatal autopsy cases of arthrogryposis were studied by gross morphology, microscopic histopathologic examination, and whole genome sequencing of postmortem DNA. Two stillborn sibling fetuses with arthrogryposis, pterygia, and amyoplasia had compound heterozygous pathogenic variants in NEB. A neonate with a histopathologic diagnosis of nemaline myopathy had a heterozygous de novo pathogenic variant in ACTA1. Another stillborn infant with pterygia and arthrogryposis had a heterozygous de novo likely pathogenic variant in BICD2. These cases demonstrate the utility of whole genome sequencing as the principal diagnostic method of lethal forms of skeletal muscle disorders that present with arthrogryposis and muscle amyoplasia/hypoplasia. Molecular diagnosis provides an opportunity for studying patterns of inheritance and for family counseling concerning future pregnancies.

YAP and the Hippo pathway in pediatric cancer.

The Hippo pathway is an important signaling pathway that controls cell proliferation and apoptosis. It is evolutionarily conserved in mammals and is stimulated by cell-cell contact, inhibiting cell proliferation in response to increased cell density. During early embryonic development, the Hippo signaling pathway regulates organ development and size, and its functions result in the coordinated balance between proliferation, apoptosis, and differentiation. Its principal effectors, YAP and TAZ, regulate signaling by the embryonic stem cells and determine cell fate and histogenesis. Dysfunction of this pathway contributes to cancer development in adults and children. Emerging studies have shed light on the upregulation of Hippo pathway members in several pediatric cancers and may offer prognostic information on rhabdomyosarcoma, osteosarcoma, Wilms tumor, neuroblastoma, medulloblastoma, and other brain gliomas. We review the results of such published studies and highlight the potential clinical application of this pathway in pediatric oncologic and pathologic studies. These studies support targeting this pathway as a novel treatment strategy.

Loss of function variants in human PNPLA8 encoding calcium-independent phospholipase A2 γ recapitulate the mitochondriopathy of the homologous null mouse.

Mitochondriopathies are a group of clinically heterogeneous genetic diseases caused by defects in mitochondrial metabolism, bioenergetic efficiency, and/or signaling functions. The large majority of proteins involved in mitochondrial function are encoded by nuclear genes, with many yet to be associated with human disease. We performed exome sequencing on a young girl with a suspected mitochondrial myopathy that manifested as progressive muscle weakness, hypotonia, seizures, poor weight gain, and lactic acidosis. She was compound heterozygous for two frameshift mutations, p.Asn112HisfsX29 and p.Leu659AlafsX4, in the PNPLA8 gene, which encodes mitochondrial calcium-independent phospholipase A2 γ (iPLA2 γ). Western blot analysis of affected muscle displayed the absence of PNPLA8 protein. iPLA2 s are critical mediators of a variety of cellular processes including growth, metabolism, and lipid second messenger generation, exerting their functions through catalyzing the cleavage of the acyl groups in glycerophospholipids. The clinical presentation, muscle histology and the mitochondrial ultrastructural abnormalities of this proband are highly reminiscent of Pnpla8 null mice. Although other iPLA2 -related diseases have been identified, namely, infantile neuroaxonal dystrophy and neutral lipid storage disease with myopathy, this is the first report of PNPLA8-related disease in a human. We suggest PNPLA8 join the increasing list of human genes involved in lipid metabolism associated with neuromuscular diseases due to mitochondrial dysfunction.

Altered pulmonary lymphatic development in infants with chronic lung disease.

Pulmonary lymphatic development in chronic lung disease (CLD) has not been investigated, and anatomy of lymphatics in human infant lungs is not well defined. Hypothesis. Pulmonary lymphatic hypoplasia is present in CLD. Method. Autopsy lung tissues of eighteen subjects gestational ages 22 to 40 weeks with and without history of respiratory morbidity were stained with monoclonal antipodoplanin and reviewed under light microscopy. Percentage of parenchyma podoplanin stained at the acinar level was determined using computerized image analysis; 9 CLD and 4 control subjects gestational ages 27 to 36 weeks were suitable for the analysis. Results. Distinct, lymphatic-specific staining with respect to other vascular structures was appreciated in all gestations. Infants with and without respiratory morbidity had comparable lymphatic distribution which extended to the alveolar ductal level. Podoplanin staining per parenchyma was increased and statistically significant in the CLD group versus controls at the alveolar ductal level (0.06% ± 0.02% versus 0.04% ± 0.01%, 95% CI -0.04% to -0.002%, P < 0.03). Conclusion. Contrary to our hypothesis, the findings show that there is an increase in alveolar lymphatics in CLD. It is suggested that the findings, by expanding current knowledge of CLD pathology, may offer insight into the development of more effective therapies to tackle CLD.

Large multifocal cardiac myxoma causing the sudden unexpected death of a 2-month-old infant--a rapidly growing, acquired lesion versus a congenital process?: a case report.

We report the occurrence of a clinically undiagnosed biatrial myxoma with left ventricular involvement in a 2-month-old male infant, resulting in sudden death. During a routine well-baby examination, a grade (34) holosystolic murmur was detected at the left sternal border with radiation to the axilla and back. On the following day, the patient collapsed and died suddenly. An autopsy revealed a large multifocal neoplasm diffusely involving the aortic valve while displaying mitral, tricuspid, and left ventricular extensions. The ensuing histopathologic and immunohistochemical studies were diagnostic for myxoma. We discuss the occurrence of cardiac myxoma within the pediatric population and review the literature as to theorize whether this lesion was a congenital process versus a rapidly growing tumor that developed after the child was born. Lastly, we address the potential for sudden death in patients with such tumors.

Papillary glioneuronal tumor: a case report and review of the literature.

Papillary glioneuronal tumor is a recently described central nervous system neoplasm that almost always occurs adjacent to the lateral ventricle. We present a case of this rare entity, representing the 21st case of this lesion, which exhibits a mixed astrocytic and neuronal differentiation. This case was an incidental finding in a young woman who presented secondary to a traumatic injury to the left eye. Histologic evaluation after surgical removal showed a cystic tumor consisting of 2 distinct components: a unique pseudopapillary architecture admixed with foci of solid areas. The pseudopapillae were composed of thick hyalinized vessels enclosed by a single layer of glial fibrillary acid protein-positive astrocytes and variously sized synaptophysin-positive and chromogranin-negative neuronal cells in the interpapillary regions. Abundant Rosenthal fibers, foci of calcification, areas of hemosiderin deposition, gliosis, areas of vascular proliferation associated with piloid gliosis, and chronic inflammatory infiltrate were identified. The combination of cytologic benignity, lack of necrosis, and low proliferative index as evidenced by immunohistochemistry using antibody to Ki-67 confirmed the low malignant potential of this tumor. Knowledge and precise classification of this entity are important to avoid unnecessary use of chemo- and/or radiotherapy for treatment.

Altered expression of pro-inflammatory and developmental genes in the fetal brain in a mouse model of maternal infection.

Human studies of unexplained cerebral palsy (CP) suggest an association with maternal infection. We used an established model of maternal infection, lipopolysaccharide (LPS) administration, to investigate the molecular changes in the fetal brain that may link maternal infection and CP. We compared gene expression in brains from mouse pups exposed to LPS in utero to those from saline-treated controls. Dams were injected with 50 microg LPS or saline on E18 with surgical delivery from 0.5 to 6h later. Differential gene expression was analyzed in the whole mouse brain using RT-PCR. When compared to control mice, pups exposed to LPS showed increased expression of pro-inflammatory genes monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta), as well as VEGF, a regulator of vascular development and permeability, the anti-apoptotic protein Y-box-binding protein-1 (YB-1), and the neuronal differentiation factor necdin. LPS-exposed mice also showed downregulation of semaphorin 5b and groucho, involved in axon guidance and neurogenesis, respectively, providing evidence that LPS may disrupt normal developmental pathways. These data suggest possible mechanisms for adverse neurological outcomes following maternal infection involving elevated cytokine levels and altered expression of developmental genes in the fetal brain.

Eye abnormalities in Fryns syndrome.

Fryns syndrome is a rare, generally lethal, autosomal recessive multiple congenital anomaly (MCA) syndrome first described in 1979. Patients with the syndrome present with the classical findings of cloudy cornea, brain malformations, diaphragmatic defects, and distal limb deformities. Over 70 patients have been reported revealing a wide variety of phenotypic features. Although initially considered a major feature of Fryns syndrome, cloudy cornea has been relegated as a minor diagnostic sign and not commonly reported in patients since the original description. However, eye findings per se are not uncommon. Abnormal eye findings occasionally reported in Fryns syndrome potentially result in amblyopia and blindness, profoundly affecting neurologic outcome of those who survive the neonatal period. We reviewed 77 reported patients with Fryns syndrome and summarized the abnormal eye findings identified in 12 of the reported cases. In addition, we contribute three new patients with Fryns syndrome, one of which demonstrated unilateral microphthalmia and cloudy cornea.

Newborn with anophthalmia and features of Fryns syndrome.

We report a newborn female with craniofacial malformations, bilateral anophthalmia, large abnormally shaped ears, short neck, small distal phalanges and nails, left diaphragmatic hernia, hypoplastic optic nerves, severe pulmonary hypoplasia, and an accessory spleen, and describe the autopsy findings. The infant expired at 18 h of life. The features were most consistent with Fryns syndrome although other conditions were considered including Matthew Wood syndrome. Anophthalmia, to our knowledge, has not been reported previously in Fryns syndrome; however, eye findings are common, particularly microphthalmia and cloudy cornea.

Fetal hydrops and familial pulmonary lymphatic hypoplasia.

Two siblings were born with pleural effusions and hydrops. The first infant was a 26-week-old gestation male and died at 8 hours of life with radiographically small lungs and pulmonary insufficiency. No lung tissue was obtainable. This pregnancy was followed by two normal term infants, a male and female. The fourth pregnancy resulted in a female born at 35 weeks' gestation with pleural effusion and hydrops who died at 32 months of age. This infant was discharged from hospital at 32 days of age with small pleural effusions, but needed supplemental oxygen and daily diuretics to control edema. There were 14 additional admissions until death-all for respiratory distress or infections. An open lung biopsy at 2 months, showed dilated pleural lymphatics, with hypoplasia of the acinar and terminal bronchiolar lymphatics. At postmortem examination there was a markedly thickened pleura, and slit-like hypoplastic lymphatics of the acinar and terminal bronchioles and interlobular septal regions. This is the second family reported with these distinctive pulmonary intra-acinar and peri-acinar hypoplastic lymphatics. This disease is compatible with an autosomal recessive mode of inheritance.