Erythrocyte glutathione synthetase deficiency leads not only to glutathione but also to glutathione-S-transferase deficiency.

Glutathione synthetase (GSH-S) is one of the two known hereditary causes of glutathione deficiency. We describe a family whose two children have hemolytic anemia. The children's erythrocytes lack GSH and are severely deficient in GSH-S activity. No neurologic findings or 5-oxoprolinuria were present. A concurrent deficiency of glutathione-S-transferase (GST) was also detected in the erythrocytes. Residual glutathione could be detected in the erythrocytes using a sensitive cycling assay. The deficiency was found to be most severe in reticulocyte-depleted preparations. The GSH-S activity of the erythrocytes of the parents was one-half normal, while the glutathione S-transferase activity was normal. We conclude that the primary defect is one of GSH-S. Glutathione stabilizes GST in vitro, and it is assumed that the deficiency of GST in the erythrocytes of the patients is due to the instability of this enzyme in the absence of adequate intracellular GSH levels.

Endomyocardial biopsy to monitor anthracycline therapy in children.

Evaluation of the ultrastructure of material obtained by endomyocardial biopsy has been proposed as a means to evaluate patients for impending anthracycline cardiotoxicity. Eighteen biopsies obtained from 13 patients (age, 3-18 years) are reported. Twelve biopsy procedures were done to evaluate the cardiac status on reaching a cumulative dose of 400 mg/m2 and three patients had six subsequent biopsies after having received significantly more drug or receiving radiation therapy to the lungs or mediastinum. Scores were assigned to the tissue obtained and used to guide the decision to continue or stop anthracycline therapy. Three patients with abnormal cardiac studies at low cumulative doses, five of whom had received greater than 400 mg/m2 and three of whom had received considerably higher doses and thoracic irradiation were given more drug without incident. Two specimens were interpreted to indicate avoidance of further anthracycline and two patients were cautiously given more despite evidence of mild myocardial damage. These results indicate that endomyocardial biopsies can be performed on a pediatric population with a reasonable complication rate. Further studies should be undertaken to evaluate its usefulness as a means to predict and avoid anthracycline cardiomyopathy.

Silent infarcts in children with sickle cell anemia and abnormal cerebral artery velocity.

BACKGROUND: A substantial minority of neurologically normal children with sickle cell disease have lesions consistent with cerebral infarction as seen on magnetic resonance imaging (MRI). OBJECTIVES: To determine if transfusion therapy affects the rate at which silent infarcts develop and to evaluate the contribution of MRI of the brain to stroke prediction by transcranial Doppler (TCD) ultrasonography. STUDY DESIGN: Children with elevated TCD ultrasonographic velocity were randomized to receive long-term transfusion therapy or standard care. Magnetic resonance imaging of the brain was obtained at randomization, annually, and with clinical neurologic events. The risk for new silent lesions and/or stroke was compared for each treatment arm. RESULTS: Among the 37% of subjects with silent infarcts, those receiving standard care were significantly more likely to develop new silent lesions or stroke than were those who received transfusion therapy. For subjects receiving standard care, those with lesions at baseline were significantly more likely to develop stroke or new silent lesions than those whose MRI studies showed no abnormality. CONCLUSIONS: Transfusion therapy lowers the risk for new silent infarct or stroke for children having both abnormal TCD ultrasonographic velocity and silent infarct. However, those with both abnormalities who are not provided transfusion therapy are at higher risk for developing a new silent infarct or stroke than are those whose initial MRI showed no abnormality. The finding of a silent infarct reinforces the need for TCD ultrasonographic screening and consideration of transfusion therapy if the abnormalities are seen. Similarly, elevated TCD ultrasonographic velocity warrants MRI of the brain because children with both abnormalities seem to be at increased risk for developing new silent infarct or stroke.

Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia.

PURPOSE: Blood pressure in individuals who have sickle cell disease has been reported to be lower than published normal values. We determine whether and to what degree this is true, using data obtained as part of a large natural history study. PATIENTS AND METHODS: Blood pressure was measured annually for 3,317 subjects with sickle cell disease who were 2 years old or older. Values obtained were compared with those reported by the National Health and Nutrition Examination Survey I and II (NHANES I and II). They were further analyzed with respect to age, sex, height, weight, hematologic diagnosis, blood urea nitrogen and creatinine, stroke, and death. RESULTS: Blood pressure was significantly lower in subjects with sickle cell anemia than published norms for age, race, and sex, a difference that increased with age. It correlated with body mass index, hemoglobin, measures of renal function and age, but the strength of the correlation varied among age and sex subgroups. The risk for occlusive stroke increased with systolic but not diastolic pressure. Mortality was related to elevated blood pressure in males (P < 0.05) and to a lesser extent in females (P = 0.10). In subjects with hemoglobin SC disease, blood pressure also deviated from normal but to a lesser degree. CONCLUSION: Blood pressure is generally lower than normal in individuals with sickle cell anemia. Those with high values relative to this population had an increased risk of stroke and death. Blood pressure should be monitored but values obtained must be assessed relative to the lower values expected for patients with this disease. Those with blood pressure values above 140/90 mm Hg should be evaluated and considered for treatment.

Congenital malaria: a rare cause of splenomegaly and anemia in an American infant.

A 38-day-old infant had fever, jaundice, hepatosplenomegaly, and a hemolytic anemia. A peripheral blood smear demonstrated intraerythrocytic malarial parasites identified as Plasmodium vivax. Maternal and infant sera contained antibodies to this species. A directed history revealed the mother had suffered several febrile illnesses in Mexico during her pregnancy. Malaria had not been diagnosed nor was it considered at the time of her delivery at this hospital. Review of this and six other cases of congenital malaria reported in this country since 1950 indicates clinical manifestations seldom appear before 3 weeks of age. Although these signs are more frequently associated with other transplacental infections, their occurrence in an infant whose mother is from or who has traveled in an endemic area should prompt consideration of the diagnosis of congenital malaria.

Cognitive functioning and brain magnetic resonance imaging in children with sickle Cell disease. Neuropsychology Committee of the Cooperative Study of Sickle Cell Disease.

OBJECTIVE: Brain magnetic resonance imaging (MRI) and neuropsychological evaluations were conducted to determine whether neuroradiographic evidence of infarct in children with sickle cell disease between ages 6 and 12 years would result in impairment in cognitive and academic functioning. METHOD AND DESIGN: Children enrolled in the Cooperative Study of Sickle Cell Disease were evaluated with brain MRI and neuropsychological evaluation. Completed studies were obtained for 194 children, 135 with HbSS. MRIs were categorized according to the presence of T2-weighted, high-intensity images suggestive of infarct and were further categorized on the basis of a clinical history of cerebrovascular accident (CVA). An abnormal MRI but no clinical history of CVA was classified as a silent infarct. Neuropsychological evaluations included assessment of both global intellectual functioning and specific academic and neuropsychological functions. RESULTS: Central nervous system (CNS) abnormalities were identified on MRI in 17.9% of the children (22.2% of children homozygous for HbS), and a clinical history of CVA (N = 9, 4.6%) was identified in only children with HbSS disease. Subsequent analyses examined only children with HbSS. Children with a history of CVA performed significantly poorer than children with silent infarcts or no MRI abnormality on most neuropsychological evaluation measures. Children with silent infarcts on MRI performed significantly poorer than children with no MRI abnormality on tests of arithmetic, vocabulary, and visual motor speed and coordination. CONCLUSIONS: These results substantiate the importance of careful evaluation, educational planning, and medical intervention for CNS-related complications in children with sickle cell disease.

Risk of human immunodeficiency virus type 1 infection among sexual and nonsexual household contacts of persons with congenital clotting disorders.

The status of human immunodeficiency virus type 1 (HIV-1) infection at the time of transmission to sexual contacts remains poorly defined. Transmission to nonsexual household contacts has appeared to be rare. A total of 505 sexual and nonsexual contacts of HIV-1-infected hemophiliacs in 349 households was observed. At entry, 10% of 201 sexual partners were anti-HIV-1-positive. Follow-up of 151 uninfected partners during a total of 351 person-years of observation showed no sero-conversions, although there were 13 pregnancies during that period. Eighty-seven percent of the seronegative respondents to a detailed questionnaire reported unprotected sexual contact at least occasionally. Among 304 other household members, including 108 parents who helped administer clotting factor concentrates to their children, none was seropositive at entry. Follow-up of 263 showed no seroconversions during a total of 605 person-years of observation. Thus, anti-HIV-1-positive hemophiliacs transmitted to their partners earlier in their course but were not found to do so when prospectively observed. No relationship to level of viremia as indicated by CD4 count, HIV-1 p24 antigenemia, or acquired immunodeficiency syndrome was found. Anti-HIV-1-positive hemophiliacs had not transmitted to their nonsexual household contacts before study entry and did not do so subsequently, indicating that the risk from even close nonsexual contact is extremely low.

Homozygous protein S deficiency due to a one base pair deletion that leads to a stop codon in exon III of the protein S gene.

Homozygous protein S (PS) deficiency is a very rare disorder that causes purpura fulminans in affected newborns. This report describes the molecular genetic abnormality of a severe PS deficient child who developed purpura fulminans shortly after birth. The mutation was identified as a deletion of one adenine in codon 43 of exon III of the PROS 1 gene. This mutation results in a frameshift and a novel stop codon at position 45. The proband was apparently homozygous and his mother heterozygous for this mutation. The proband's father was not available for study. The single base pair deletion predicts a truncated translation product, where Lys 43 and Tyr 44 have been replaced by Asn 43 and Thr 44. This putative protein (predicted mw of 5.696 daltons) contains only the gammacarboxyglutamic acid (Gla) domain and the aromatic stack.

Reference values and hematologic changes from birth to 5 years in patients with sickle cell disease. Cooperative Study of Sickle Cell Disease.

OBJECTIVE: To examine hematologic changes from birth to 5 years of age and establish hematologic reference values for infants and children with sickle cell disease. RESEARCH DESIGN: Prospective natural history study. SETTING: Nineteen pediatric sickle cell centers across the United States. PATIENTS: Six hundred ninety-four infants with sickle cell disease (sickle cell anemia, sickle cell-hemoglobin C disease, and sickle-beta-thalassemia) who were enrolled in the Cooperative Study of Sickle Cell Disease at younger than 6 months of age. Median follow-up time through 5 years of age was 4.1 years. MEASUREMENTS AND RESULTS: We present longitudinal analyses of total hemoglobin concentration, percent fetal hemoglobin values, mean corpuscular volumes, total bilirubin concentration, and red blood cell (RBC), "pocked" RBC, white blood cell, platelet, and reticulocyte counts. Anemia was apparent by 10 weeks of life in infants with sickle cell anemia (SS infants). This anemia was associated with a rising reticulocyte count consistent with a hemolytic process. The reticulocyte count of SS infants increased steadily, exceeding 12% at 5 years of age. The fetal hemoglobin concentration of SS infants declined more slowly than that of infants with sickle cell hemoglobin C disease (SC infants). Pocked RBC counts rose sharply after 6 months of age, and by 1 year, 28% of SS infants had abnormal counts, above 3.5%, indicating poor splenic function. At 3 years of age, 78% of SS patients and 32% of SC patients had abnormal pocked RBC counts. The SS patients with concurrent alpha-thalassemia had, after 6 months of age and throughout early childhood, a slightly higher mean total hemoglobin concentration and lower mean pocked RBC and reticulocyte counts than SS patients without alpha-thalassemia. The hematologic profile of SC infants more closely resembled that of normal black infants, but there was mild anemia (10.5 g/dL) and slightly elevated mean values for reticulocytes (3%) and fetal hemoglobin (3%) during early childhood.

The influence of infant and maternal sickle cell disease on birth outcome and neonatal course.

OBJECTIVE: To compare the influence of maternal hemoglobin phenotype as well as that of the infant on birth outcome and neonatal complications. RESEARCH DESIGN: Prospective, natural history study with retrospective chart review for neonatal complications. SETTING: Nineteen pediatric sickle cell centers across the United States. PATIENTS: Four hundred eighty infants with sickle cell disease (SCD) who were enrolled in the Cooperative Study of Sickle Cell Disease at less than 6 months of age, as well as a comparison cohort of 118 infants with sickle cell trait born to women with sickle cell anemia in the Cooperative Study. RESULTS: In the SCD cohort, overall rates of preterm (< 37 weeks), low-birth-weight (< 2500 g), and small-for-gestational age births were 9%, 10%, and 8%, respectively; no significant differences were found according to infant hemoglobin phenotype. Term births accounted for 59% of the infants with low birth weight, significantly higher than the 41% US rate for black low-birth-weight infants (P = .014). Expectant mothers with sickle cell anemia are 2.5 times more likely to bear newborns who are small for gestational age than are women with other types of sickle cell disease, sickle trait, or C-trait. The most common prepartum and neonatal complications in infants with SCD were jaundice (25%), fetal distress (13%), anemia (10%), and respiratory distress (6%). Complication rates did not differ significantly by hemoglobin phenotype in the infants with SCD, but infants born to women with sickle cell anemia had higher rates of jaundice (P < .0001). CONCLUSIONS: Rates of adverse birth outcomes and neonatal complications in infants with SCD are similar to the rates for normal infants, although preterm birth accounts for fewer of the low-birth-weight outcomes among newborns with SCD relative to US black newborns. The hemoglobin phenotype of infants with SCD does not influence birth outcome and neonatal course, but infants born to women with sickle cell anemia are at greater risk of preterm birth, low birth weight, being small for gestational age, and neonatal jaundice.

The spectrum of brain MR abnormalities in sickle-cell disease: a report from the Cooperative Study of Sickle Cell Disease.

PURPOSE: To define the spectrum of abnormalities in sickle-cell disease, including infarction, atrophy, and hemorrhage, that are identified by brain MR imaging. METHODS: All MR studies included T1, T2, and intermediate pulse sequences. Images were interpreted without knowledge of the clinical history or neurologic examination findings. Brain MR imaging was performed in 312 children with sickle-cell disease. RESULTS: Seventy patients (22%) had infarction/ischemia and/or atrophy, infarction/ischemia was noted in 39 children (13%) who had no history of a stroke (the "silent" group). The prevalence rates for silent lesions were 17% for sickle-cell anemia and 3% for hemoglobin sickle-cell disease. For patients with sickle-cell anemia and a history of cerebrovascular accident, infarction/ischemia lesions typically involved both cortex and deep white matter, while silent lesions usually were confined to deep white matter. Within the age range studied, the prevalence of infarction/ischemia did not increase significantly with age, although older patients with lesions had more lesions than did younger patients with lesions. CONCLUSIONS: Brain MR imaging showed infarction/ischemia in the absence of a recognized cerebrovascular accident in 13% of patients. The prevalence of these lesions did not increase significantly between the ages of 6 and 14 years, suggesting that lesions are present by age 6. However, the increase in the average number of lesions per patient with age may indicate progressive brain injury.

Stroke in children with sickle cell anaemia: aetiology and treatment.

Cerebral infarction is a frequent, severe complication of sickle cell anaemia. During childhood, most strokes are due to infarction with the majority resulting from occlusion of the large cerebral arteries. Risk factors include transient ischaemic attacks, acute chest syndrome, severe anaemia and elevated blood pressure. Less certain is the association with leucocytosis, or protection provided by alpha-thalassaemia or fetal haemoglobin. Children who have one stroke are at significant risk for having subsequent events that can be substantially reduced by maintaining haemoglobin S below 30%. It has not yet been possible to identify individuals for whom transfusion can be safely stopped. Haemosiderosis is a consequence of intensive and long term transfusion therapy, which requires chelation with deferoxamine. Iron accumulation can be minimised using erythrocytapheresis but this is technically difficult in children, expensive and results in increased donor exposure. In addition to lesions associated with strokes, an additional 17% of patients can be shown to have clinically silent cerebral infarcts. Although these are termed 'silent', those affected have mild neuropsychological deficits. Their relationship to stroke or risk for recurrence is unknown. Transfusion therapy has been shown to provide primary stroke prevention for children who have elevated cerebral artery velocity. Finally, intracranial haemorrhages, more commonly found in adults, also affect children. Subarachnoid haemorrhage is frequently found to result from cerebral artery aneurysms. A condition that mimics the moyamoya syndrome radiographically, as well as for its risk of haemorrhage, can be found in children with partly occluded cerebral arteries either as a result of stroke or silent infarct.

Survey of pain management therapy provided for children with sickle cell disease.

A questionnaire was sent to principal investigators of NIH-sponsored clinical research in sickle cell disease. Twenty of 21 respondents indicated they used parenteral narcotic analgesics for pain episodes sufficiently severe to warrant hospitalization. Eleven used meperidine; seven, morphine; and one each, nalbuphine, hydromorphone, and acetaminophen with codeine. They gave the agents at frequent, regular intervals or by continuous infusion. A total of 41 of more than 3,500 patients required chronic transfusion for pain control. Complications included meperidine-associated convulsions reported by nine respondents and addiction by six. This information indicates that vigorous pain-control methods are used at institutions having a special interest in providing medical care for children with sickle cell disease.

Hospitalizations for painful episodes: association with school absenteeism and academic performance in children and adolescents with sickle cell anemia.

Painful episodes have been identified as one of the most frequent manifestations of sickle cell anemia (hemoglobin HbSS). This retrospective study compared the frequency of hospitalization and the academic performance of two groups of children with HbSS (ages 8 to 18 years) with differing frequencies of pain. A high frequency (HF) group (n = 10) was composed of children who had four or more hospitalizations for pain in the study period; those in the low frequency (LF) group (n = 11) had one or no hospitalizations for pain during the study period. The two groups were matched on age (within 6 months), gender, and ethnicity. Standardized assessments of academic achievement and school records of attendance and class grades were obtained for all participants. The standardized academic achievement for both groups was approximately one standard deviation below the normative mean of the population sample, and class grades were below a C average. School absence was frequent in both groups (LF mean = 16.8 days/year; HF mean = 35.4 days/year), and children in the HF group had significantly more absences than children in the LF group. The lack of difference in academic performance between the two groups suggests that there may be factors other than school absenteeism that affect academic achievement, which require further investigation.

Increased incidence of bacteremia in Haitian children with sickle cell anemia.

Children with sickle cell anemia who were less than 5 years old were observed over a three-year period. Those born to recent Haitian immigrants accounted for 108.4 patient-years. They had seven episodes of Streptococcus pneumoniae bacteremia and five due to Haemophilus influenzae for rates of 6.5 and 4.6 episodes per 100 patient-years, respectively. Children born to American parents were observed for 131.3 patient-years and had three episodes and one episode, respectively, for rates of 2.3 and 0.76 episodes per 100 patient-years. The differences in the overall rate of bacteremia were significant (P less than .015). Leukocyte counts and percentage of erythrocytes with pits, indicating decreased splenic function, were similar for the two groups. The Haitian families had lower annual incomes, but values for both groups were so low that their difference is unlikely to be related to the increased infection rate. Although no cause for the higher rate of bacteremia could be found, the approach to febrile illness in Haitian children with sickle cell anemia should be even more aggressive than usual. In addition to Haemophilus influenzae immunization, antibiotics effective against penicillin-resistant species should be used in the initial antibiotic coverage of their febrile illnesses.

Severe iron deficiency anemia.

Severe iron deficiency anemia remains a continuing major health hazard among inner city children in Los Angeles. Over a 24-month period, 60 children in whom hemoglobin values were below 7 grams per dl were admitted to hospital; 11 (18 percent) of them were in overt congestive heart failure. Contrary to the popular conceptions, two thirds of the anemic children were undernourished, approximating the 16th percentile for weight on the Iowa growth chart, and the frequency of premature birth was not greater than in the general population. There were no deaths in this series. A management protocol which included partial exchange transfusion of children in congestive heart failure and supportive transfusion for children with hemoglobin levels below 5 grams per dl was employed.