Multipoint linkage analysis of steroid sulfatase (X-linked ichthyosis) and distal Xp markers.

Six families with steroid sulfatase deficiency (STS; X-linked ichthyosis) have been studied with the Xg blood group (XG) and the DNA markers dic56 (DXS143), 782 (DXS85), pD2 (DXS43), and GMGX9. Carrier status of females was determined by assay of STS in hair roots. GMGX9 detects a frequent restriction fragment length polymorphism and also identifies a deletion in the majority of families with STS deficiency, including five of the six reported here. The linkage relationship of this marker to the others was studied in normal three-generation families yielding 32 phase-known meioses informative for two or more markers. No recombinants were observed between STS and GMGX9, giving a maximum lod score of 8.73 at zero recombination. Multipoint linkage analysis taking STS and GMGX9 as a single locus and incorporating two-point marker data and STS-XG data from published studies gave the map (Sequence: see text). This order was 2.4 times more likely than with (STS,GMGX9) and dic56 reversed and is supported by our findings in a male with steroid sulfatase deficiency due to a deletion of Xp22.3 which encompasses the XG locus. He is deleted for GMGX9 but shows normal hybridization to dic56 and 782.

A comparison of dopamine and homovanillic acid excretion, as prognostic indicators in malignant phaeochromocytoma.

The urinary excretion of dopamine and its metabolite homovanillic acid (HVA) were compared in 15 patients with malignant phaeochromocytoma. Six patients with increased dopamine and HVA excretion had disseminated malignancy and the poorest prognosis. Four patients with increased urinary dopamine levels but normal HVA excretion also had widespread metastases and poor prognosis. The best prognosis was for 5 patients who had normal excretion of dopamine and HVA, and minimal disease. When dopamine and HVA excretion were considered separately, it was found that duration of survival was significantly better for patients with normal dopamine excretion than those with increased dopamine excretion (p less than 0.003). There was no significant difference in survival time between patients with normal and increased HVA excretion. In this study dopamine excretion appeared to be a more discriminating biochemical index of malignancy, prognosis and disease progression than HVA excretion.

A re-evaluation of dopamine excretion in phaeochromocytoma.

In a re-evaluation of the use of dopamine as a prognostic factor in phaeochromocytoma, a series of 34 patients was imaged with iodine-131-meta-iodobenzylguanidine, a radiopharmaceutical specifically localized in chromaffin tumours. Fourteen patients were found to have malignant disease. Increased dopamine excretion was found in 9 (64%) of these patients including all four with primary intra-adrenal tumours, and this was associated with a poor prognosis. Of the five patients in the malignant group with normal dopamine excretion on referral, the disease extent was minimal and in four the primary tumour had been resected. Twenty patients appeared to have benign phaeochromocytoma from the imaging results. Of these, 16 were intra-adrenal and four were extra-adrenal. In 19 the dopamine excretion was within the control range but in one it was marginally increased. From these observations it would seem that dopamine excretion may be a useful prognostic factor when combined with imaging to determine the extent of the disease.

The origin of 45,X males.

Maleness in association with the karyotype 45,X is a very rare and hitherto unexplained condition previously described in only four or five patients. This study was carried out to determine whether such males might actually possess Y-chromosomal material. Of the two 45,X males studied, one was found to be a low-grade mosaic with a 46,XY karyotype in less than 3% of fibroblasts; all lymphocytes karyotyped were 45,X. Fibroblast DNA from this individual was found to contain Y-specific repeated sequences in 1%-3% the amount observed in the father, consistent with mosaicism for a 46,XY cell line. No Y-specific repeated sequences were detected in the other patient, in whom all mitoses were 45,X. In neither patient were there detectable amounts of any of the single-copy Y-specific DNA sequences for which we tested. Studies of Xg blood groups and of X-linked restriction fragment length polymorphisms indicated that the single X chromosome was of maternal origin in both 45,X male probands. In contrast to the situation in XX males, we can exclude paternal X-Y interchange as the etiology in the cases described here. Our findings are compatible with mosaicism being the explanation of at least some "45,X" males.

New approach to the localisation of phaeochromocytoma: imaging with iodine-131-meta-iodobenzylguanidine.

Thirty eight patients with known or suspected phaeochromocytoma were studied by radioisotope imaging after intravenous administration of iodine-131-meta- iodobenzylguanidine (131I- mIBG ), a radiopharmaceutical which has affinity for chromaffin tumours. Seventeen positive results (including one false positive) and 21 negative results (including two false negatives) were obtained. Clinical accuracy was 92%. Urinary noradrenaline concentrations were raised in all patients with confirmed phaeochromocytoma. These findings show that 131I- mIBG is of value in localising and assessing the extent of chromaffin tumours.

Genetic evidence of X-Y interchange in a human XX male.

Of the hypotheses put forward to explain why occasional individuals with two X chromosomes are nonetheless male, the one that has attracted most attention is the possibility that one of the X chromosomes has obtained a small piece of Y chromosome which is sufficient to produce 'maleness'. This hypothesis was based primarily on the observation that in two families with XX males both fathers were Xg(a+) and both probands Xg(a-). (Xg shows X-linked dominant inheritance.) This theory holds that an anomalous X-Y interchange at meiosis in the father resulted in the paternal X chromosome's losing the Xg gene and acquiring a male-determining gene from the Y chromosome. While, for example, the frequencies of Xg phenotypes among XX males and the cytogenetic observation of a structural abnormality in one X are compatible with this hypothesis, direct evidence of it is lacking. Here we describe an XX male who expresses his father's allele for 12E7, a Y-linked marker, but fails to express his father's allele for Xg, an X-linked marker. These findings strongly suggest that anomalous X-Y interchange occurred in this case and perhaps in that of many other XX males. We suggest that a male-determining gene on the Y has also been translocated to the X and caused maleness in the proband. These results are discussed in the light of current models of X-Y chromosomal homology.

On the standard error of the probability of a particular diagnosis.

Approximate standard errors of the probability of a particular diagnosis are given for the predictive and estimative methods described by Aitchison and Dunsmore. An example used in the detection of carriers of Duchenne muscular dystrophy (DMD) is given for illustration.

Creatine kinase activity in the detection of carriers of Duchenne muscular dystrophy: comparison of two methods.

Serum creatine kinase activity was estimated in 48 control women and 22 female carriers of Duchenne muscular dystrophy by two different methods. One method is based on the colorimetric determination of creatine liberated from creatine phosphate; the other, an N-acetyl cysteine activated UV system, was used in an automated mode. The two methods were equally efficient in carrier detection, and results were closely correlated over the range of values encountered in controls and carriers. Log creatine kinase values appeared to be normally distributed in controls, but the distribution in carriers appeared skewed towards its upper end. If both distributions are assumed to be Normal, the probability, together with its standard error, that a consultand is a carrier, can be calculated from her creatine kinase value, and if the latter is expressed in standard deviation units of the control log creatine kinase distribution, probability estimates can be compared between laboratories.

Evidence for the lack of a carrier effect in the solvent extraction and determination of octopamine by gas chromatography mass spectrometry.

It has been shown that there is no significant carrier effect when low levels of [3H]octopamine (100 pg) are extracted by ethyl acetate from aqueous solutions containing a 10(3) or 10(6) times excess of unlabelled octopamine. It is also shown that there is no carrier effect when low levels of octopamine as the tetrakis-TMS derivative are injected with 100 times the amount of the [2H3] analogue on an SE 30 column.

Two populations of Rh groups together with chromosomally abnormal cell lines in the bone marrow.

At the onset of his disease a man with polycythaemia vera had chromosomally normal cells in the bone marrow and Rh blood group CDe/cDE. Five years later he developed pancytopenia with erythroid hyperplasia of the bone marrow. This was associated with the presence of a major abnormal clone, 45,XY,B-,C-,16+, a minor clone, 45,XY,2+,3-,C-, and a few apparently normal cells. At the same time Rh blood grouping showed two populations of red cells, one CDe/cDE and one giving the reactions of CDe/CDe which can be interpreted as CDe. If monosomic CDe be the correct interpretation the case provides a strong hint that the Rh complex locus is sited either on the long arm of a B-group chromosome or, less probably, on an autosome of the C group.