Homozygous mutation in ELMO2 may cause Ramon syndrome.

We report on a girl, born to first cousin Lebanese parents, with intellectual disability, seizures, repeated gingivorrhagia, enlarged lower and upper jaws, overgrowth of the gums, high arched and narrow palate, crowded teeth, hirsutism of the back, large abdomen and a small umbilical hernia. Cysts of the mandible, fibrous dysplasia of bones, and enlarged adenoids causing around 60% narrowing of the nasopharyngeal airways were noted at radiographic examination. Her brother presented with the same features in addition to a short stature, an ostium secundum, and more pronounced intellectual disability. He died at the age of 8 years from a severe pulmonary infection and repeated bleeding episodes. A clinical diagnosis of Ramon syndrome was made. Whole exome sequencing studies performed on the family revealed the presence of a novel homozygous missense mutation in ELMO2 gene, p.I606S in the affected individuals. Loss of function mutations in ELMO2 have been recently described in another clinically distinct condition: primary intraosseous vascular malformation or intraosseous hemangioma, called VMOS. Review of the literature and differential diagnoses are discussed.

Mineral density of hypomineralised enamel.

OBJECTIVES: To characterize molar-incisor hypomineralisation (MIH) defects of different severities quantitatively and qualitatively using X-ray microtomography (XMT) and to measure the range of reduction in mineral density (MD) of MIH enamel compared with the normal range. METHODS: Ten sound teeth and ten MIH teeth were scanned using a commercial XMT system. Four hydroxyapatite phantoms of different densities were used as calibration standards with each scan. A calibration equation derived from the phantoms with each tooth was used for MD calibration. MD was traced from the cementum-enamel junction (CEJ) to the cusp tip and from the dentine-enamel junction (DEJ) to the outer enamel surface. RESULTS: In sound teeth, MD increased from CEJ to cusp/incisal tip, while in MIH teeth MD dropped from the CEJ to the occlusal region, then increased again at the cusp tip. MD was highest midway between DEJ and outer enamel in sound teeth. In MIH, enamel showed normal thickness and MD was highest near the DEJ and then decreased towards the outer enamel. MD of MIH enamel was on average about 19% lower than sound enamel. The MIH defects seemed to follow the incremental lines of enamel formation. CONCLUSIONS: MIH defects are hypomineralised defects of different severities that follow the natural incremental lines of enamel formation. Cuspal areas are usually only mildly affected and cervical enamel always appears to be sound.

Relationship between laser fluorescence and enamel hypomineralisation.

OBJECTIVES: To study the relation between the mechanical properties of hypomineralised enamel, and its laser fluorescence (LF). METHODS: Five extracted teeth with molar-incisor hypomineralisation (MIH) were sectioned longitudinally through the defects and polished to prepare the hypomineralised enamel for testing. Hardness (H) and elastic modulus (E) of enamel were measured using nanoindentation. Measurement recording started from the cervicoenamel junction and proceeded occlusally in increments of 200 microm. Laser fluorescence readings were taken along the same line and at the same sites using a DIAGNOdent pen. RESULTS: H, E, and LF readings from cervical enamel were within the expected range for normal sound enamel. After log transformation of the H and E measurements to allow for linear correlation analysis, there was a significant and moderately strong inverse correlation between LF and H or E samples (r (between specimens)=0.59, r (between specimens)=0.39, respectively; p<0.001). CONCLUSIONS: This study shows that, in the absence of dental caries, increased DIAGNOdent readings can indicate enamel hypomineralisation. While the increased LF readings in carious enamel are thought to be related to the presence of caries bacterial metabolites, the increased readings in hypomineralised enamel may be related to proteins in the hypomineralised enamel and/or light scattering by the inhomogeneous enamel.

Novel mutation in the gamma-glutamyl carboxylase gene resulting in congenital combined deficiency of all vitamin K-dependent blood coagulation factors.

A mutation in the gamma-glutamyl carboxylase gene leading to a combined congenital deficiency of all vitamin K-dependent coagulation factors was identified in a Lebanese boy. He is the first offspring of consanguineous parents and was homozygous for a unique point mutation in exon 11, resulting in the conversion of a tryptophan codon (TGG) to a serine codon (TCG) at amino acid residue 501. Oral vitamin K(1) administration resulted in resolution of the clinical symptoms. Screening of several family members on this mutation with an RFLP technique revealed 10 asymptomatic members who were heterozygous for the mutation, confirming the autosomal recessive pattern of inheritance of this disease. In 50 nonrelated normal subjects, the mutation was not found. This is the second time a missense mutation in the gamma-glutamyl carboxylase gene is described that has serious impact on normal hemostasis.

Immunotoxins against CD19 and CD22 are effective in killing precursor-B acute lymphoblastic leukemia cells in vitro.

Monoclonal antibodies (Mabs) conjugated to toxins or their subunits (immunotoxins or ITs) are undergoing clinical testing in adults with a variety of malignancies. The potential impact of this form of therapy in pediatric precursor B-lineage acute lymphoblastic leukemia (pre-B ALL) has yet to be determined. Mabs directed against the cell surface antigens, CD19 and CD22 conjugated to deglycosylated ricin A chain (dgRTA) have been tested in patients with non-Hodgkin's lymphoma (NHL), but not in patients with pre-B ALL. Because of the encouraging performance of these ITs in phase I trials, we evaluated the specific cytotoxicity of anti-CD19 (HD37-dgRTA) and anti-CD22 (RFB4-dgRTA) ITs or their combination (Combotox) on patient-derived pre-B ALL cells maintained in vitro on a stromal feeder layer. After 48 h in culture, cytotoxicity to tumor cells was determined by flow cytometry using propidium iodide (PI) and fluorescein isothiocyanate (FITC)-conjugated anti-CD10, 19, and 22. Both RFB4-dgRTA and HD37-dgRTA induced a statistically significant reduction in the number of viable leukemic cells, and Combotox was even more effective. Our results demonstrate that these ITs are specifically cytotoxic to primary pre-B ALL cells and that they should be further evaluated for the therapy of B-lineage ALL.

Parameningeal alveolar rhabdomyosarcoma with an isolated pancreatic metastasis.

A 15-year-old girl with alveolar rhabdomyosarcoma of the paranasal sinuses was found to have a solitary visceral metastatic focus in the pancreas. This unusual occurrence is presented and discussed.

Correlation of serum cholylglycine level with hepatic dysfunction in children with sickle cell anemia.

Hepatic dysfunction occurs commonly in children with sickle cell disease (SCD). Although the etiology is multifactorial, cholestasis is a prominent feature. Serum cholylglycine (CG) has been found to be a very sensitive indicator of cholestasis. Our objective was to determine whether CG levels are elevated in children with SCD and whether they are predictive of hepatic dysfunction. Blood samples were obtained from 97 children with SCD. Liver function tests were done and serum CG concentrations were measured. Patients were followed up for 2 years. Thirty-eight percent of the patients had an elevated CG level. During the 2 years of follow-up, 16% of the children with a previously elevated CG level developed abnormal liver function test results or required a cholecystectomy as compared with 13% with a previously normal CG level (p = 0.92). We conclude that although CG level was elevated in 38% of the patients with SCD, it did not appear to predict liver dysfunction during the ensuring 2 years.

Treatment of pediatric Hodgkin's disease with chemotherapy alone or combined modality therapy.

Optimal treatment for Hodgkin's disease during childhood is unknown. We report the treatment outcome of patients with Hodgkin's disease <13 years of age seen at the American University of Beirut Medical Center (AUBMC) between 1980 and 1996. A retrospective review of the medical records of 24 children treated for HD at AUBMC was performed. Treatment consisted of chemotherapy alone (n = 15) or chemotherapy plus involved field radiotherapy (n = 9). Chemotherapy consisted of COPP, ABVD, or alternating cycles of each for a total of 6 to 12 cycles, depending on clinical and radiological response; three patients received MOPP. Five patients in the chemotherapy group had clinical stage (CS) I and II and 10 had CS III disease. In the combined modality group, eight patients had CS I and II and one had CS IV disease. At a median follow-up of 5 years, the event-free survival (EFS) for the combined modality group was 100% and the overall survival (OS) 100%. For the chemotherapy alone group, the EFS was 56% and the OS was 79%. Four patients (27%) in the chemotherapy alone group who had Stage IIIB disease relapsed. Mean time to relapse was 4.3 years. In our experience, six cycles of COPP or (COPP plus ABVD) alone were suboptimal for the treatment of Stage IIIB Hodgkin's disease patients, especially those with involvement of lower abdominal nodes (III2B), extensive pulmonary disease, or mixed cellularity histology. Radiation therapy or additional chemotherapy courses are required for these patients.

The development of monoclonal antibodies for the therapy of cancer.

Monoclonal antibodies (Mabs) were first described by Köhler and Milstein in 1975. Not only did this discovery lead to a Nobel prize, but it created an enormous scientific field that has now become a multimillion dollar industry. Mabs made the transition from laboratory reagents to clinical diagnostics very quickly. However, their development as therapeutic agents was, as predicted, more costly and time-consuming. Indeed, clinicians and scientists were required to learn a new set of rules for using these large, immunogenic, targeted agents in humans. Nevertheless, in 1997 the first Mab was licensed in the U.S. and several others will soon follow. In this review, we discuss Mab-based strategies for the treatment of cancer. We compare native, fragmented, recombinant and chimeric antibodies, bispecific antibodies, immunoconjugates, and immunoliposomes. The rationale for their development, their advantages, their in vitro and in vivo performance, and their clinical usefulness are discussed.

Safety and cost-effectiveness of outpatient total body irradiation in pediatric patients undergoing stem cell transplantation.

PURPOSE: To determine the feasibility, safety, and cost of delivering total body irradiation (TBI) in an outpatient setting. PATIENTS AND METHODS: The records of 33 pediatric patients with hematopoietic malignancies undergoing TBI in preparation for bone marrow transplantation (BMT) at the Children's Medical Center of Dallas between February 1992 and June 1997 were retrospectively reviewed. Seventeen children received TBI in an outpatient setting, including 7 patients younger than 8 years of age. All patients had a good performance status (Karnofsky index > 90%) and lived or were housed within a 50-mile radius of the hospital. Patients received 1200 cGy or 1350 cGy in 8 or 9 fractions twice daily over 4 to 5 days and were admitted for high-dose chemotherapy after the last TBI fraction. Mean age was 9 years (range 13 months to 16 years). Close contact was maintained with the BMT staff during outpatient TBI. RESULTS: Eleven patients (65%) received oral ondansetron for nausea and vomiting, 6 received promethazine and ondansetron, and 3 required dexamethasone. Only 2 of the 17 children (12%) required admission during TBI for persistent vomiting and poor oral intake. Two other children (12%) required outpatient administration of intravenous fluids. The other 13 patients (76%) tolerated the outpatient TBI regimen well. Taking into account hospitalization and ambulance transport charges, outpatient TBI represented a savings of approximately $3250 per patient compared with inpatient TBI. CONCLUSIONS: Fractionated TBI delivered in an outpatient setting to selected children of all ages is a safe and cost-effective practice.

Comparison of laparoscopic and open splenectomy in children with hematologic disorders.

OBJECTIVE: To compare laparoscopic and traditional open splenectomy in children with nonmalignant hematologic disorders. STUDY DESIGN: Retrospective review of 36 consecutive nonrandomized splenectomies (16 laparoscopic and 20 open) performed for hematologic disorders at a single pediatric institution during the past 3 years. The two-sided Mann-Whitney U test for non-parametric variables was used for statistical analysis. RESULTS: An open procedure was performed on 20 patients (mean age, 9.7 years), five of whom had a concomitant cholecystectomy. A laparoscopic splenectomy was performed on 16 children (mean age, 10.3 years), seven of whom had a concomitant cholecystectomy. The mean anesthesia and operative times were longer in the laparoscopic than in the open group (p < 0.001). However, the mean number of hours of postoperative analgesia was less in the laparoscopic group (p < 0.005). Patients who had laparoscopic splenectomy were also discharged home earlier (p < 0.01) and resumed a regular diet sooner. Mean operating room charges were higher in the laparoscopic group (p < 0.001), but total hospitalization costs were not significantly different. Postoperative complication rates were similar. The hematologic response was comparable. CONCLUSIONS: laparoscopic splenectomy is feasible and safe in children with hematologic disorders. Although it currently requires more operative time than the open approach, it is superior with regard to duration of postoperative analgesia, duration of hospital stay, and recovery of bowel function.