Adrenal hypoplasia congenita (AHC) can occur due to deletions or mutations in the DAX 1 (NR0B1) gene on the X chromosome (OMIM 300200). This form of AHC is therefore predominantly seen in boys. Deletion of the DAX 1 gene can also be part of a larger contiguous deletion including the centromeric dystrophin and glycerol kinase (GK) genes. We report a girl with a de novo deletion at Xp21.2 on the maternal chromosome, including DAX1, the GK gene and 3′ end of the dystrophin gene, who presented with salt losing adrenal insufficiency and moderate developmental delay, but relatively mild features of muscular dystrophy. Investigation using the androgen receptor as a marker gene identified skewed inactivation of the X chromosome. In the patient’s leucocytes, the paternal X chromosome was completely inactive, but in muscle 20% of the active chromosomes were of paternal origin. Thus skewed X inactivation (deletion on the active maternal X chromosome with an inactive paternal X chromosome) is associated with AHC in a female. Variability in X inactivation between tissues may account for the pronounced salt loss and adrenal insufficiency but mild muscular dystrophy.
Molecular deletion screening with cDNA probes from the dystrophin gene was undertaken in patients with Becker muscular dystrophy from 58 separate families. Deletions were found in 41 (71%) of these families. Thirty-four (83%) of the deletions started in the same intron near the centre of the gene, and although there was no precise correlation between clinical severity and deletion pattern, the commonest deletion pattern, which was present in 49% of ali deletion families, is associated with a mild phenotype.Becker muscular dystrophy (BMD) has been a major interest of this department since 1981, and we were among the first to show that BMD and Duchenne muscular dystrophy (DMD) were likely to be allelic.'The cloning of the DMD/BMD gene,2 and the discovery of its protein product, dystrophin,3 has confirmed that mutations in the same gene are indeed responsible for the clinical spectrum of DMD/BMD, but the details of how the varying severity of phenotypes can be explained by differences in the underlying mutation are not yet fully worked out, though some progress has been made.4 Study of BMD, with its greater range of clinical severity and relative homogeneity of molecular deletions, is likely to be more fruitful than study of DMD, where a more narrowly defined phenotype is produced by a wide range of molecular deletions. Several groups have already described series of DMD deletions, '0 but few have included large series of BMD patients. 1 " We
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