Southern blotting was performed with cDNA probes for the human von Willebrand factor (vWF) gene on six patients with severe type III von Willebrand's disease (vWD). A partial deletion in the 3′ end of the vWF gene was demonstrated in one individual whose parents were related and who had an alloantibody inhibitor to vWF. A resulting novel 2.0- kilobase (kb) EcoRI fragment was used for carrier detection within the patient's family, and seven carriers of this recessive trait were identified. Of the six tested, five had normal or only slightly reduced levels of vWF antigen, but with generally higher levels of factor VIII. The sixth carrier had moderately severe vWD and it is proposed that this patient is heterozygous for the defective vWF gene and a second recessive vWF defect. The novel 2.0-kb EcoRI restriction fragment was cloned and sequenced, and compared with that of the corresponding normal 4.2-kb EcoRI fragment that includes exons 41 and 42 of the vWF gene. A deletion of 2,320 base pairs (bp) which included exon 42, was identified and a novel 182-bp insert was found between the breakpoints. This insert was detected by polymerase chain reaction amplification both in the patient's DNA and in his carrier relatives.

Carefully designed access to nationally funded GH replacement in GH-deficient adults was associated with a significant improvement in quality of life over a 3-year period with mean daily GH doses lower than in the majority of previously reported studies.

Carrier detection was attempted in 50 haemophilia A kindred by means of restriction fragment length polymorphism (RFLP) analysis using two linked and three intragenic probes. The sample comprised 330 individuals including 70 haemophiliacs, 45 obligate carriers and 100 possible carriers. Non-related haplotypes contained within the sample group were used to tabulate the intragenic RFLP allele frequencies. The linkage disequilibrium existing between the XbaI and Bc1I RFLP was shown to be less than previously reported, such that 69% of women are informative for at least one of these two polymorphisms. 36 women were subsequently diagnosed as carriers and 37 as being normal: in 52 of these, diagnosis was based either on intragenic RFLPs or linked RFLP plus strong phenotypic data, and was considered to be unequivocal; in the remaining 21, diagnosis was based on linked RFLPs alone and was considered to be probabilistic, with a 5-10% possible error rate. 27 of the possible carriers, either from families with sporadic haemophilia or from families where missing members precluded haplotype analysis, remained unassigned. 72% of the obligate carriers and firmly diagnosed carriers were heterozygous and phase known for at least one intragenic RFLP, whereas 6% were uninformative for the RFLPs for which they were examined. In 54 informative meioses, three recombinations between the factor VIII locus and the DX13 and/or ST14 loci were observed, giving a recombination rate of 5.5%. 15 prenatal diagnoses were carried out. Of the 11 male fetuses, six were shown to be affected and five to be normal. In three of four prenatal diagnoses where only a linked RFLP was informative, the result was confirmed by fetoscopy, fetal blood sampling, and factor VIII assay.

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