X-linked lymphoproliferative disease: prenatal detection of an unaffected histocompatible male.

Chorionic Villous Biopsy (CVS) for diagnosis of XLP was undertaken at 10 weeks gestation in an obligate carrier. The fetus was found to be male by cytogenetic analysis. XLP (Xq25-q26) is closely linked to the RFLP markers DXS10, DXS37 and DXS42, but only DXS10 (distal to XLP) was informative for prenatal diagnosis in this family. RFLP analysis using this marker gave a 7% risk that the fetus was affected, based on the known recombination frequency between DXS10 and XLP. Further investigation was then undertaken to obtain a rapid and more accurate diagnosis using the three highly polymorphic PCR based markers. These were the AC repeat markers DXS424 (XL5A) and DXS425 (XL90A3) and the tetramer repeat marker within HPRT. DX425 is approximately 10 cM proximal to DXS10 and HPRT but is not known with certainty to map proximal or distal to XLP. DXS424 is proximal to DXS10 and HPRT and was inferred to be proximal to XLP on the basis of map distance from HPRT estimated by linkage analysis of data from CEPH pedigrees. This was confirmed by a recombinant in the XLP family between DXS424 and DXS425, placing DXS424 proximal to XLP. Diagnosis by linkage using DXS424 and DXS425, at least one of which is proximal to XLP, and distal markers DXS10 and HPRT, increased the accuracy of diagnosis using flanking marker analysis to greater than 99% that the fetus was unaffected. HLA DR typing of the CVS showed that the fetus was DR identical to a male sibling with XLP. HLA compatibility was confirmed at delivery by full HLA typing and MLC.(ABSTRACT TRUNCATED AT 250 WORDS)

Report on the X-linked lymphoproliferative disease in an Australian family.

X-linked lymphoproliferative disease is characterized by immune deficiency, particularly to the Epstein-Barr virus and by a tendency to develop fatal infectious mononucleosis, acquired hypogammaglobulinaemia or malignant lymphoma. This disorder has been diagnosed in three boys, two brothers and a maternally related cousin, residing in Australia. The proband presented at 6 years of age with fulminating infectious mononucleosis. His 9 year old male cousin had developed an ileal Burkitt lymphoma one year earlier. Immunological and molecular genetic evidence is presented to support our view that his younger sibling is also affected with this condition. DNA linkage studies using probes to DXS10 and DXS37 provide confirmatory evidence for the diagnosis in the proband's brother and information on carrier status in female family members.

Plasmapheresis in children with Guillain-Barré syndrome.

Between 1987 and 1989, we plasmapheresed six children with Guillain-Barré syndrome (GBS). None of the children could walk independently at the start of the treatment, and one was being ventilated. Five patients showed clinical improvement during pheresis, and no significant side effects occurred. The median time from onset of weakness to independent walking for these six children was 17 days. This compares with 43 days for 18 children with GBS in this institution who were given supportive measures only.

Sustained normalization of cardiac function by chelation therapy in thalassaemia major.

The effect of iron chelation using subcutaneous desferrioxamine on the iron-overloaded heart was studied prospectively over 4 years in 23 asymptomatic patients (mean age 13.2 +/- 5.3 years) with thalassaemia major and transfusion-dependent anaemia. The haemoglobin was maintained greater than 10 g/dl by transfusion and chelation therapy to achieve a negative iron balance. Chelation was closely supervised to ensure compliance. Despite an increase in calculated iron load due to transfusion from 34 +/- 27 g to 63 +/- 28 g, there was a sequential fall in serum ferritin levels from 3148 +/- 1956 ng/ml to 2228 +/- 1825 ng/ml (P less than 0.05). Abnormalities of left ventricular (LV) function, assessed by radionuclide angiography, were present at rest or during exercise in 18 of 23 patients (78%) prior to therapy. Normal LV function was restored in 11 of these 18 patients, five continuing to have abnormal function and two dying. There was a significant increase in resting LVEF from 50 +/- 8% to 57 +/- 6% (P less than 0.01). Peak exercise LVEF rose from 51 +/- 11% to 65 +/- 7% (P less than 0.001). We conclude that the common subclinical abnormalities of LV function induced by iron overload in unchelated patients with thalassaemia major can be reversed with long-term subcutaneous infusions of desferrioxamine.

A study on the value of red cell exchange transfusion in transfusion dependent anaemias.

We compared red cell exchange transfusions (RC Ex) on the Aminco Celltrifuge (continuous flow cell separator) with conventional transfusions in 17 patients aged between 7 and 24 years who have transfusion dependent homozygous beta-thalassaemia and two other patients with chronic transfusion dependent anaemias aged 20 and 22. We aimed to return the youngest cohort of cells ('Neocytes') from both donor blood and the patient and to discard older cells ('gerocytes'). Using RC Ex, red cell transfusion requirement was reduced by 30%, reducing significantly the iron load, and the transfusion interval was increased by 43%. There is a great demand by the patients to continue this therapy as they have appreciated the immediate benefit of reduced hospitalization.

A new application of plasma exchange in insulin dependent diabetes mellitus.

An insulin dependent diabetic patient was resistant to all but central venous insulin administration. For this reason plasma exchange was tried and it restored insulin responsiveness. An anti-insulin IgG antibody was identified in the patient's plasma. Plasma exchange reduced antibody levels and these correlated with daily insulin requirements. Kinetic analysis of anti-insulin antibodies, however caused us to doubt that they were the sole cause of the problem. Although the mechanism remains unclear, plasmapheresis proved to be an effective method of treating this patient's insulin resistance.

Early left ventricular dysfunction and chelation therapy in thalassemia major.

Exercise radionuclide angiography was used to assess the incidence of subclinical abnormalities of left ventricular function in 23 asymptomatic patients with thalassemia major. Left ventricular ejection fraction (LVEF) at rest was normal in 18 patients and abnormal in 5. A normal LVEF response during exercise was shown in only 5 of the patients with normal resting left ventricular function. A normal response during exercise occurred more often in those patients who had received a smaller transfusional iron load and had a lower serum ferritin level (p less than 0.05). Twelve of the twenty-three patients were receiving chelation therapy with subcutaneous deferoxamine. Ejection fraction at rest was normal in 11 of these patients. During exercise a normal ventricular response was shown in 4 patients. After 1 year of intensive chelation therapy in these 12 patients, left ventricular function was reassessed. A normal exercise response was seen in an additional 4 patients; 3 of these showed an increase in peak exercise LVEF, and in the remaining patient no change of peak exercise LVEF was shown. The response during exercise was unchanged in 3 patients and had deteriorated in 1 patient.

Community-initiated screening programme for beta-thalassaemia trait.

Seven hundred and ninety-five people, (96% of whom were of Greek origin) were screened for thalassaemia trait. A prevalence rate of 7.1% for beta-thalassaemia carriers was found. The red cells of individuals with the alpha-1-thalassaemia, beta-thalassaemia, and haemoglobin Lepore traits all had a mean corpuscular volume (MCV) of less than 76 fL and a mean corpuscular haemoglobin (MCH) of less than 25 pg, thus confirming the usefulness of these indices as a preliminary thalassaemia screening test. However, in three of the six people provisionally diagnosed as having delta-beta-thalassaemia trait, an overlap of MCV and MCH values with the normal range occurred. Community attitudes to the survey and its implications are discussed.

Homozygous beta-thalassaemia in a part-Aboriginal Australian.

We describe here the first case of classical homozygous beta-thalassaemia in a part-Aboriginal child. The child came from Bourke, New South Wales, and is the product of a consanguineous mating. His great-great-grandfather was a camel driver from Sri Lanka who settled in western New South Wales. From the family studies, we have found that there are now 17 carriers of beta-thalassaemia in the Aboriginal community in northwestern New South Wales, and it is anticipated that more part-Aboriginal children with thalassaemia major will be identified. The presence of numerous carriers of beta-thalassaemia in the Aboriginal population would suggest that care should be taken in the administration of iron for the treatment of anaemias found in Aboriginal children.

Haematological aspects of antenatal diagnosis for thalassaemia in Britain.

The results are described of 200 antenatal diagnostic tests for haemoglobinopathies performed on samples of fetal blood obtained during the second trimester of pregnancy. Haemoglobin A synthesis in the fetus was measured by incorporation of tritiated leucine in vitro and separation of the globin chains on CM23 columns. The range of HbA synthesis detected was 3.5-8.0% in normal fetuses, 2.0-5.0% in fetuses with thalassaemia trait, and less than 1.6% in fetuses with thalassaemia major. There were eight cases in which other haemoglobinopathies were diagnosed. 29% of the pregnancies were terminated because thalassaemia major was diagnosed, and 9.5% of the remaining healthy fetuses were lost for obstetric reasons. Follow up has been possible for 96% of the 124 surviving babies and three misdiagnoses have come to light; one false positive (0.5%) and two false negatives (1%). These figures represent a first effort at antenatal diagnosis for haemoglobinopathies and it is likely that they will improve with the passage of time.

Rhodotorulic acid--investigation of its potential as an iron-chelating drug.

The use of rhodotorulic acid (RA) as an iron-chelating drug was suggested by experiments in hypertransfused rats in which urinary and fecal iron excretion were significantly enhanced in response to RA. The toxicity of the drug appears to be minimal at a parenteral dose less than 250 mg/kg. An increased excretion of zinc was the only notable side effect of the drug at the doses used. When administered i.v. to humans, RA was only 16% more effective than desferrioxamine (DF). Pharmacokinetic studies showed that RA persisted in the bloodstream of dogs 6 times longer than desferrioxamine after an intravenous injection. Accordingly RA was evaluated as a potential repository drug. While animal experiments were encouraging, human subjects experienced a painful local reaction to RA administered either i.m. or s.c. as a suspension in physiological saline. Accordingly it appears that RA is best looked at as a second line drug, unless a means can be found to obviate local inflammatory reactions.