Submandibular TCD approach detects post-bulb ICA stenosis in children with sickle cell anemia.

BACKGROUND: Transcranial Doppler (TCD) ultrasound is a procedure commonly used to screen individuals with the major hemoglobin S diseases, Hb SS and Hb S-beta(0), for significant stenoses in the circle of Willis. Flow velocities above 200 cm/s have been shown to identify patients at elevated risk for cerebral infarction. Among TCD's limitations is the inability to insonate the distal extracranial, petrous, and cavernous internal carotid artery (ICA) through the standard transtemporal approach. METHODS: We extended the submandibular approach to include infra-siphon portions of the ICA. RESULTS: Using the extended submandibular approach to evaluate these portions of the ICA, we identified stenotic lesions in 4 patients with Hb SS disease out of a population of 131 children with Hb SS. Three of the 4 patients had no history of overt stroke or stroke-like symptoms. Neuroimaging confirmed the stenotic lesions, and also revealed watershed infarction as well as discrete areas of silent infarction. All 4 children had neuropsychological impairment. CONCLUSIONS: The submandibular approach, when added to a standard transcranial Doppler examination, may increase the sensitivity of this technique to identify important potential sources of cerebral infarction.

Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA).

Iron deficiency is usually attributed to chronic blood loss or inadequate dietary intake. Here, we show that iron deficiency anemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a type II transmembrane serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin. These findings demonstrate that TMPRSS6 is essential for normal systemic iron homeostasis in humans.

Sickle cell disease complicated by post-streptococcal glomerulonephritis, cerebral hemorrhage and reversible posterior leucoencephalopathy syndrome.

A patient with homozygous hemoglobin SS disease presented with an intracerebral hemorrhage complicating reversible posterior leucoencephalopathy syndrome (RPLS), secondary to hypertension associated with acute post-streptococcal glomerulonephritis (APSGN). Distinguishing potentially reversible causes of central nervous system events from primary cerebral infarction or hemorrhage in patients with sickle cell disease is important because the management and prognosis of these complications is very different. Similarly, because of the difference in prognosis between APSGN and other forms of sickle cell nephropathy, it is also important to differentiate these conditions.

Iron studies in infants born to an iron overloaded mother with beta-thalassemia major: possible effects of maternal desferrioxamine therapy.

A 30-year-old woman with transfusion-dependent, homozygous beta-thalassemia major and transfusional hemosiderosis had 2 successful pregnancies after ovulation induction and in vitro fertilization. Treatment with subcutaneous desferrioxamine (DF) was discontinued before the conception but restarted at 6 months of gestation. Elective cesarean section was performed at 35 weeks of pregnancy because of partial placenta previa. The infant was clinically normal. At the time of delivery, the maternal serum ferritin was 2000 ng/mL, serum iron/iron binding capacity (SI/TIBC) were 274/380 microg/dL, and % saturation 72%. Serum ferritin level in the infant was 42 ng/mL, SI/TIBC were 53/222 microg/dL, and % saturation 23%. During a twin pregnancy 2 years later, DF therapy was totally withheld. Elective cesarian section was performed at 36 weeks of gestation. Both twins were clinically normal. At delivery, the maternal serum ferritin was 1700 ng/mL, SI/TIBC 447/450 microg/dL, and % saturation 99%. Serum ferritins of the twins were 227 and 203 ng/mL, SI/TIBC were 30/182 and 27/203 microg/dL, and % saturations 16% and 13%. Despite elevated iron studies in the mother during both pregnancies, the SI/TIBC of the infants were quite low. In the first pregnancy in which DF was administered in last months of gestation, a low level of serum ferritin was present in the newborn that was even lower at 3 months of age. In the second pregnancy, high normal, levels of ferritin were present in both twin newborns. Despite comparable gestational ages, hemoglobin levels were lower in the first pregnancy than the second. These studies indicate that very high maternal levels of SI/TIBS and serum ferritin were not associated with increased fetal SI/TIBC, which were, in fact, quite low. Because of the different fetal ferritin levels in the 2 pregnancies, it is possible that treatment of the mother with DF in the last weeks of pregnancy may have resulted in depletion of fetal iron stores.

Newborn screening coupled with comprehensive follow-up reduced early mortality of sickle cell disease in Connecticut.

To assess the impact of newborn screening (NBS) on the mortality of children with sickle cell anemia, we analyzed the Connecticut death certificates of all children less than 15 years old at death. We compared sickle cell-related deaths in three periods: 1970-1988 when there was no state NBS; between 1988 and 1990 when there was limited state NBS; and 1990-2002 when universal NBS was in effect in Connecticut. In the period 1988-2002, we identified all death certificate records in which sickle cell anemia was listed as a cause of death and compared these with children who were shown to have sickle cell anemia (Hb SS and sickle-beta(o) thalassemia) by the state's NBS programs. In the 11-1/2 years after universal NBS was initiated in Connecticut in 1990, there were no reported deaths among infants diagnosed at birth with Hb SS or sickle-beta(o) thalassemia. In the 18 years before any State NBS (1970-1988) there were 13 deaths attributed to sickle cell diseases. The limited State NBS program conducted between 1988 and July 2000 missed testing five affected children who subsequently died. These results document a marked reduction in mortality since the introduction of NBS for hemoglobinopathies and suggest that the Connecticut NBS program, coupled with comprehensive follow-up care, greatly reduced mortality.

History of pediatric hematology oncology.

Pediatric Hematology Oncology as a specialty was possible because of the evolution of the science of Hematology, which developed microscopy for describing blood cell morphology and methods for quantitation of these elements. Before pediatric blood diseases could be defined, it was necessary to establish the normal blood values of infancy and childhood. The unique features of the blood of the newborn were the focus of many of the early studies. After normal values were established, specific blood disease and hematologic syndromes of children began to be described in Europe and the United States. Pediatric Hematology Oncology is a broad and complex area that encompasses perturbations of the several-formed elements of the blood and their precursors in the bone marrow, as well as the coagulation-fibrinolytic systems in the plasma, the reticuloendothelial system, and malignancies of the blood and solid tissues and organs. The interactions of the blood and nutrition have long been important areas of study. Advances in Pediatric Oncology have been particularly spectacular in the last 50 years. Using multi-modal therapy including combination chemotherapy, more than 80% of children with cancer can now be cured. During the last 50 years, Pediatric Hematology Oncology has increasingly used tools of the "new biology": immunology, biochemistry, enzymology, genetics and molecular genetics, and others. During the last century, many diseases have been recognized and defined by biochemical and genetic mechanisms, and in some instances they have been prevented or cured.

Pediatric grand rounds: a tribute to Norman J. Siegel, M.D.

At ceremonies held in Baltimore Maryland on May, 4, 2002, Dr. Howard A Pearson, Professor of Pediatrics, was awarded the John A. Howland award of the American Pediatric Society, probably the most prestigious award of American Pediatrics. Dr. Pearson had been nominated for the award by Dr. Norman Siegel. The Department of Pediatrics Grand Rounds on Wednesday noon, October 26, 2002 was originally scheduled as a repetition of the presentation by Dr. Siegel and the acceptance by Dr. Pearson for those who could not be in Baltimore. However; in a number of meetings, unknown to Dr. Siegel, it was unanimously decided that it would be very appropriate to instead honor him as he stepped down from his position as Vice- and Interim Chairman of Pediatrics, and to formally thank him for his long and faithful service to the Department of Pediatrics, the Yale University School of Medicine, and the Yale New Haven Hospital.