Boy with pseudohypoparathyroidism type 1a caused by GNAS gene mutation (deltaN377), Crouzon-like craniosynostosis, and severe trauma-induced bleeding.

We report on a 6-month-old boy with craniosynostosis, pseudohypoparathyroidism type 1a (PHP1A), and a GNAS gene mutation. He had synostoses of the coronal, frontal, and sagittal sutures, brachyturricephaly, and hydrocephaly. He also had congenital hypothyroidism, round face, full cheeks, shortness of limbs, mild developmental delay, and muscular hypotonia. Because of progressive hydrocephaly, the synostosis was corrected surgically but circulatory decompensation led to disseminated intravascular coagulation and cerebral infarctions. Our patient died 8 days later. Postmortem molecular studies of GNAS, the gene for guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (gene for PHP1A), identified a de novo heterozygous 3 bp in frame deletion predicting a deletion of the asparagine residue at position 377 (deltaN377). This is the second report of this mutation. Results of molecular studies of craniosynostosis genes (FGFR2, FGFR3) and of numerous genetic variants predisposing to bleeding disorders were normal. We question whether craniosynostosis and trauma-induced bleeding disorder may be manifestations of PHP1A, or if our patient had two or three different congenital disorders.

Oral topotecan in children with recurrent or progressive high-grade glioma: a Phase I/II study by the German Society for Pediatric Oncology and Hematology.

BACKGROUND: Continuous oral treatment with topotecan may be more effective than the typical 1-day and 5-day treatment schedules. In previous studies of continuous treatment with topotecan, increased intestinal side effects were reported in adult patients; however, the experience in pediatric patients and patients with high-grade glioma is quite limited. METHODS: Thirty-two pediatric patients with recurrent high-grade glioma (16 females and 16 males; median age, 9.5 years) were enrolled in the current Phase I/II study. Tumor locations included the cerebral cortex (n = 5), pons (n = 18), and other sites (n = 9). An injectable formulation of topotecan was administered orally, in ice-cold orange juice, once daily. The starting dose of 0.4 mg/m(2) per day was escalated on a patient-by-patient basis. At each patient's maximum dose, blood samples were obtained for the determination of plasma hydroxytopotecan and topotecan lactone concentrations and for the calculation of pharmacokinetic quantities. RESULTS: The toxicity criteria for a maximum tolerated topotecan dose were met in only 19 patients. The primary toxicity type was hematologic. The median maximum tolerated dose was 0.9 mg/m(2) per day (n = 19). The calculated maximum total plasma topotecan concentration was 3.8 ng/mL (n = 7), with an area under the concentration-time curve of 38.4 ng. hours/mL and a half-life of 4.1 hours, which would result in the complete disappearance of topotecan from the plasma after 12 hours. Objective responses were observed in 2 of 13 evaluable patients and lasted for 2.5 and 9 months, respectively (continuous clinical remission, 1 of 14 patients; partial response, 2 of 14 patients; stable disease, 7 of 14 patients; progressive disease, 4 of 14 patients). CONCLUSIONS: Oral topotecan (median dose, 0.9 mg/m(2) per day) administered once daily was well tolerated and somewhat effective in children with recurrent high-grade glioma. A schedule in which the daily dose is split so that dosing is performed twice daily may be superior to the current schedule.