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The family of two siblings with severe hereditary spherocytosis was investigated. The decrease was evident on both the α- and the β-chains. The parents were haematologically normal. The mother was heterozygous for the low-expression polymorphic allele αLEPRA. The father was heterozygous for a novel combination in which one allele showed the α-spectrin low expression polymorphic allele αLELY, while his other allele showed the αLELY polymorphism in cis with a G → A substitution, named Bicére, found at the extreme 3′ end of exon 51. This combination was designated αLELY-Bicére. The children were compound heterozygotes for alleles αLEPRA and αLELY-Bicére. Reverse transcription polymerase chain reaction detected only trace amounts of the mRNA coding for αLELY-Bicére. Mutation αLELY-Bicére is therefore an essentially null mutation with no functional protein product. The lack of disease in the αLELY/αLELY-Bicére father compared with the marked haemolysis in the αLEPRA/αLELY-Bicére children showed that expression of allele αLELY is not low enough to expose null α-spectrin alleles on the other chromosome. Quantitative estimations from these findings suggest that, to evoke spherocytosis, it is necessary that α-spectrin expression must be reduced to less than 25% of normal, while a reduction to 8% is sufficient. [ABSTRACT FROM AUTHOR]

Absorption of cobalamin free or bound to chicken serum was assessed in nine patients with pancreatic insufficiency. Simultaneously the in vitro effect of duodenal juice collected from six patients and seven controls was tested on labelled cobalamin complexed to chicken serum or to R salivary binder. Malabsorption of free cobalamin was observed in one of nine patients and in four of nine patients when cobalamin was administered bound to chicken serum. The in vitro effect of duodenal juice on cobalamin complexed to chicken serum or to R salivary binder was studied: the percentage of free cobalamin released was significantly decreased in pancreatic insufficiency compared with controls whatever the binder used; the degradation of R salivary binder was different in pancreatic insufficiency and in controls. Despite the in vitro abnormalities observed in pancreatic insufficiency, these did not correlate with the in vivo absorption of cobalamin which was often normal in our patients. [ABSTRACT FROM PUBLISHER]

One-hundred ten I-rose bengal studies (RBI) were performed in infants suspected of having biliary atresia. Fecal RBI excretion of less than 10% was observed in 72 of 73 cases of extrahepatic biliary atresia, but also in 10 of 37 cases of intrahepatic cholestasis of various origins. One-hundred twenty-two RBI tests were performed in children operated on for extrahepatic biliary atresia and 71 tests were performed between postsurgical weeks 3 and 8, and 51 tests were done later. Prognostically, early tests show that fecal RBI excretion of more than 15% was observed in 2 of 34 cases who were later completely jaundice-free and in only 1 of 37 cases where no bile flow restoration occurred. [ABSTRACT FROM AUTHOR]

Molecular hybridisation using cloned hepatitis B virus DNA (HBV DNA) was applied to liver and serum samples from 46 children (39 with liver diseases and seven controls) for detection of HBV DNA sequences, free and integrated into the liver cell genome. HBV DNA integration was observed in 10 children. The young age of some of these cases indicates that such integration can occur early in liver disease and is not related to the duration of viral infection. Thirteen children exhibited serological evidence of active viral multiplication. All but one had free HBV DNA in liver tissue and integrated HBV DNA sequences were found in four cases. Integrated HBV DNA sequences alone were also detected in three children with neither HBV-antigens nor HBV DNA in serum. One had inactive cirrhosis, and the two others, chronic active hepatitis. Consequently DNA hybridisation may be useful for diagnosis, in the absence of serological signs of HBV infection; its specificity was enhanced in the present investigation by negative results in six children with autoimmune chronic active hepatitis. Taken together, the above results imply that HBV-DNA integration can occur in both active and inactive liver disease. Integrated HBV DNA was also observed in the liver of three children with fatal hepatic failure who presented with antibodies to HBsAg and/or to hepatitis B core antigen in the serum. This finding raises the question of the relationship between the host immune factors and the state of HBV DNA. [ABSTRACT FROM PUBLISHER]

Gilbert's syndrome was diagnosed in 37 patients with unconjugated hyperbilirubinaemia without overt haemolysis or structural liver abnormality, who had a marked reduction in hepatic bilirubin UDP-glucuronosyltransferase activity (B-GTA) (as compared with that of 23 normal subjects). No significant correlation existed in these patients between serum bilirubin level and the values of B-GTA, thus suggesting that factors other than a low B-GTA must influence the degree of hyperbilirubinaemia in Gilbert's syndrome. Studies of 51Cr erythrocyte survival and 59Fe kinetics in 10 unselected patients demonstrated slight haemolysis in eight, whereas mild ineffective erythropoiesis was suggested in all from a low 24-hour incorporation of radioactive iron into circulating red cells. This overproduction of bilirubin resulting from mild haemolysis and perhaps dyserythropoiesis might reflect only an extreme degree of the normal situation. It certainly contributes to the hyperbilirubinaemia of Gilbert's syndrome and may play a major role in the manifestation of this condition. [ABSTRACT FROM PUBLISHER]

Secondary to the detection of a chronic anemia with a slightly increased Hb F level in a 7-year-old boy carrying a hemoglobin (Hb) variant, we investigated the members of his family and found that they were related to the original case of Hb Calais. In the present study, we report the clinical and biological impacts of this Hb variant in various members of three generations of this family.

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome caused by germline mutations in the VHL tumor-suppressor gene. Central nervous system (CNS) and retinal hemangioblastomas are highly vascular tumors that are hallmarks of the disease. These tumors overexpress vascular endothelial growth factor (VEGF) and represent a potential target for anti-angiogenic drugs. We observed, after 3 to 4 months of treatment, secondary paradoxical polycythemia in 3 VHL patients with CNS or retinal hemangioblastomas treated by the anti-VEGF receptor SU5416. Hematocrit was normal before the beginning of the trial, and no progression of hemangioblastomas was observed. Polycythemia vera and all known causes of secondary polycythemia were also ruled out. Polycythemia has never been reported in current SU5416 trials for advanced malignancies and could express a specific action on red blood cell precursors occurring only in the absence of a functional VHL gene. These findings could also affect the inclusion of VHL patients with pre-existing polycythemia in future anti-VEGF receptor trials.

Defective lymphocyte apoptosis caused by mutations of the Fas gene can result in an autoimmune lymphoproliferative syndrome (ALPS) in humans. We report two cases of dyserythropoiesis associated with a Fas-deficient condition in childhood. In both cases, dyserythropoiesis predominated on the more mature erythroblasts, and was associated with a lymphoproliferative syndrome as well as with haemolytic anaemia, hypergammaglobulinaemia and the expansion of an unusual population of CD4- CD8- T cells that express the alpha/beta T-cell receptor. The regression of dyserythropoiesis under steroid therapy suggested that it resulted from an autoimmune mechanism, itself secondary to the lymphocyte Fas apoptosis deficiency. Fas-defective apoptosis may be a new aetiology for childhood dyserythropoiesis.

Thrombocytopenia detected during pregnancy addresses the issue of its mechanism and of the possible occurrence of neonatal thrombocytopenia. To further investigate these issues, 50 women referred to us because of thrombocytopenia detected during pregnancy (platelet count, <150 x 10(9)/L), were extensively studied, as well as their offspring. Among these thrombocytopenic women, we used the threshold of 70 x 10(9)/L to differentiate between mild and severe thrombocytopenia. Whatever the severity of thrombocytopenia, we found biological features of an autoimmune disorder in 48% of the women, and chronic thrombocytopenia in 55%. A familial thrombocytopenia was evidenced in 1 case. These 50 women gave birth to 63 neonates, among whom 24 were thrombocytopenic, either at birth or during the first week of life. Neonatal thrombocytopenia could only be predicted in multiparous women, on the basis of previous neonatal thrombocytopenia in older siblings, and/or when maternal platelet life span study, performed before pregnancy, had evidenced an autoimmune thrombocytopenia (AITP)-like profile. These results suggest that, in case of pregnancy-associated thrombocytopenia, familial and immunological studies, combined with postdelivery iterative platelet counts, should be performed to properly characterize the thrombocytopenia. Moreover, the platelet count of the neonate should be carefully assessed at birth and during the following days, a platelet life span study should be performed after delivery in the mother, because these two parameters are likely to bring valuable information regarding the forthcoming pregnancies and the risk of neonatal thrombocytopenia.

The epidemiological characteristics of iron deficiency anemia after radioimmunoassay of serum and erythrocyte ferritin were evaluated in 209 Malian women at the time of delivery in a maternity unit in Bamako, Mali. The incidence of iron deficiency anemia was high (36.8%). This incidence did not reflect socio-economic status, nor even any particular obstetric history, but was significantly higher in younger mothers (aged under 26). The severity of anemia was such that 2.4% of women would require a blood transfusion post-partum. It looks therefore desirable, in Mali, to screen routinely and to ensure the prevention of iron deficiency in adolescent girls and to include, in the prevention of anemia of pregnant women, routine iron supplements from the beginning of pregnancy.

Background: As in adults, myelodysplastic syndromes in children are often preleukemic and their spontaneous remission is exceptional., Case Reports: Case 1. A girl, aged 8 years, developed pancytopenia with macrocytic anemia. The myelogram and bone marrow biopsy showed dyserythropoiesis with macroblastosis, but without sideroblasts. The chromosome configuration was normal and the negative results of other investigations led to the diagnosis of refractory anemia without any known cause. Bone marrow transplantation was considered, but a spontaneous remission intervened and has persisted for 3 years. Case 2. A girl, aged 5 years, was investigated for worsening of a macrocytic anemia that had been present for 3 years, without changes of granulocytes and platelets. The myelogram showed dyserythropoiesis with megaloblastosis and sideroblasts. No known cause could be identified. As for the preceding patient, a spontaneous remission occurred, and has persisted for 3 years. Case 3. A girl, aged 5 months, developed pancytopenia. The myelogram showed dys-megakaryocytopoiesis. All hematologic data spontaneously normalized after 1 year, and have remained so 1 year later., Conclusion: The spontaneous remission, that has occurred in our 3 patients, has been reported in one only adult. This possibility precludes considering all the myelodysplastic syndrome in children as preleukemic, and suggests that bone marrow transplantation is not urgent in these situations.

Magnetic resonance imaging was performed to assess the subchondral bone of the knee in 64 patients with severe hemophilia A. Using this method, subchondral cysts could be detected and evaluated. We separated the cysts into four classes (LL, LH, HH, C) depending on their signal intensities on T1- and T2-weighted images. Follow-up studies, performed on 25 patients during a period of 10-30 mo after the initial examination, suggest that these four classes of cysts correspond to four successive stages. Morphological changes within a class of cysts were also observed. Although histological confirmation was not possible, this study demonstrated that magnetic resonance imaging allows a better understanding of the pathophysiology and the natural evolution of the subchondral cysts in hemophilic arthropathy.

A study of iron deficiency was carried out in two districts in Paris among 207 children aged 10 months recruited from two well-baby out-patient clinics. The main results are as follows: 12% of children were anemic, ferritin was low in 21% and 40% had a borderline deficiency, as shown by a decrease in siderophilin saturation. The average daily milk intake was greater among the immigrants, but this group, being mainly fed whole cow milk with no iron supplementation, had a lower iron intake overall. A positive correlation was found between the percentage of ingested iron-supplemented formulas and the mean corpuscular volume or serum iron levels. Iron deficiency was more frequent in children born to multiparous mothers and in the absence of any iron supplement during pregnancy. Weight gain was inversely correlated to ferritin levels, suggesting a major role of fast growth on iron metabolism.

A seroimmunologic evaluation of 57 children with chronic hepatitis is presented. Twenty-one patients had chronic persistent hepatitis and 36 had chronic active hepatitis. Serum samples obtained before treatment were tested for HBsAg, anti-HBs, anti-HBc, smooth muscle antibody, and antibody to endoplasmic reticulum. A persistently positive HBsAg was observed in the serum of 18 of the 21 patients with chronic persistent hepatitis. The chronic active hepatitis group was divided into three subgroups according to the presence of hepatitis B-virus markers (7 patients), smooth muscle antibody (10 patients), and endoplasmic reticulum antibody (9 patients). Determination of these markers could be useful for classifying children with chronic hepatitis.

The catabolism of human fragment D, (FgD), obtained by plasmin digestion of fibrinogen has been investigated in normal subjects and patients with liver cirrhosis and the results compared with those obtained for fibrinogen (Fg). Fg was labelled with I-125 and Fg D with I-131 using the chloramine T method. The plasma disappearance curves of both labelled proteins fitted a two exponential curve. In controls the plasma clearance rate of Fg D was greater than that of Fg as shown by the marked difference between the half-lives of these two tracers: 8,9 and 83,5 hours for Fg D and Fg respectively. The fractional catabolic rate of Fg D was 3.38 times the plasma pool per day. In nine patients with liver cirrhosis, catabolism of Fg was not modified. In contrast, catabolism of Fg D was significantly reduced with a half life of 13.0 hours and a low fractional catabolic rate. These results suggest the role of the liver in the catabolism of Fg D in man.

A simplified spot method for determination in serum of hepatitis B virus DNA (HBV DNA) by molecular hybridization is proposed. For simultaneous testing of 30 serum samples, it reduced to about 1 hr the duration of the steps preceding hybridization proper. The method also greatly reduced the loss of DNA during these steps and allowed more sensitive detection in samples of only 25 or 50 microliters. HBV DNA was determined in 181 serum samples by this method, and the results were pooled with 67 previous determinations by the Southern blot technique. Results for the pool were then compared to those obtained with radioimmunoassay for serological HBV markers. Ninety-six of the 248 samples were HBV DNA positive. Eleven others gave variable or inconclusive results, probably due to low viral particle titers. Seventy-two HBsAg- and HBeAg-positive sera contained HBV DNA, confirming that HBeAg is a marker of active viral replication. Fourteen other HBsAg- and HBeAg-positive sera, obtained from eight patients, were either HBV DNA negative or oscillated between negative and positive, or, again, were weakly positive; serological follow-up in 7 patients showed seroconversion to anti-HBe in 5, 3 of which became HBsAg negative. Eight of the HBsAg-positive sera were negative or borderline for HBeAg but contained HBV DNA and may, therefore, have been infective; seven of these sera had anti-HBe. Six HBsAg-negative sera contained HBV DNA and may also have been infective; five of these exhibited HBV antibodies. These results indicate that molecular hybridization not only provides a more sensitive and direct method for detecting hepatitis B virus in serum but also defines additional serological patterns with predictive or epidemiological value.

Iron deficiency (ID) at the stage of latent deficiency (LID) or frank anemia (IDA) is still common in pediatric practice. We have assessed the prevalence of LID and IDA in an infant population with an age range of 9-11 months, in Paris. Red cell indices, hemoglobin level, serum iron, transferrin saturation and serum ferritin levels were assayed. There was considerable prevalence of ID as 82% of the children exhibited low levels in one of the above parameters. We found low mean cell hemoglobin (MCH) to be predictive of LID in one third of cases. Since MCH value is routinely available to the physician, it appears that a close examination of this red cell index should allow for the diagnosis of ID in a large number of children at risk, without the need to resort to more elaborate and expensive laboratory tests.

The immunologic status of patients undergoing cardiopulmonary bypass as investigated. Rheumatoid factor, cryoglobulinemia and serum immune complexes were looked for. Studies were performed before the operation and eight or fifteen days later. From the results, it is concluded that the immunologic changes that occur in the immediate postoperative period cannot be interpreted because of the profound modifications resulting from cardiopulmonary bypass.

The effects of ranitidine, a new potent histamine H2-receptor antagonist, on gastric intrinsic factor (IF) secretion and protein-bound cobalamin absorption were evaluated in 6 patients with duodenal ulcer, before, during and after discontinuation of ranitidine therapy. Oral ranitidine (150 mg twice a day) resulted in a non significant decrease of IF concentration and IF output but was responsible for malabsorption of protein-bound cobalamin. This malabsorption was reversible upon discontinuation of ranitidine. These results indicate that occurrence of cobalamin deficiency cannot be excluded during long-term ranitidine treatment and emphasize the need for careful follow-up in these patients.

The cases of 2 children with Wilson's disease revealed by persistent hypertransaminasemia are reported. Blood ceruloplasmin concentration was low but the liver content of copper was lower than usually seen in presymptomatic forms of the disease. The apparently low liver copper concentration could be explained by an unusually important steatosis.