Functional X-chromosomal mosaicism of the skin: Rudolf Happle and the lines of Alfred Blaschko

Abstract

In this article, the contribution of Rudolf Happle to the understanding of X-linked skin diseases is reviewed. In 1977 he proposed functional X-chromosomal mosaicism as the genetic mechanism underlying cutaneous anomalies that were seen in a number of X-linked skin diseases such as incontinentia pigmenti or focal dermal hypoplasia. Moreover, he recognized that these cutaneous anomalies followed the lines of Blaschko and thus he could tie in the development of the lines of Blaschko with a datable embryonic event. Convincing proof for the concept of functional X-chromosomal mosaicism was later provided by his group from functional sweat studies in female carriers of the X-linked gene defect hypohidrotic ectodermal dysplasia showing again on the back of the patient a gross, fountain-like mosaic typical of the lines of Blaschko. Moreover, in the years 1977 to 1981 he recognized the mosaic pattern in a syndrome of chondrodysplasia punctata, linear ichthyosis, patchy cicatricial alopecia, unilateral cataracts, and short stature again as a functional X-chromosomal mosaic becoming manifest exclusively in women and proposed that this syndrome, which is today named after him, is because of an X-linked dominant gene defect. Finally, the puzzling molecular genetics of the Happle syndrome are reviewed. Most likely, the Happle syndrome gene is not lethal for hemizygously affected males but rather similar to the example of epilepsy with mental retardation limited to females, the gene actually spares male gene carriers.

Malformation syndromes caused by disorders of cholesterol synthesis

“…Skin fi ndings at birth typically include a scaling, erythematous eruption with a linear or patchy distribution that follows lines of X-inactivation, the so-called lines of Blaschko ( 236,237 ) ( Fig. 6A ).…”

Incontinentia pigmenti in a boy with XXY mosaicism detected by fluorescence in situ hybridization

“…The effects of X inactivation would manifest clinically along the lines of Blaschko, as has been proposed for female patients with IP. 11,12 The presence of a normal NEMO gene in the patient's XY cells would have allowed his survival. A second possibility is that the altered NEMO gene is present in all cells but that X inactivation in the XXY cells, which are heterozygous for the mutation, has allowed a normal copy of the NEMO gene to be expressed.…”

The Genetics of Human Skin Disease

“…Several X-linked skin diseases have been described, where the skin of males is completely affected and that of hemizygous female carriers possess patterns that often follow the lines of Blasckho. In the case of the X-linked dominant disorder, X-linked hypohidrotic ectodermal dysplasia, a skin disease that causes males to lose their ability to sweat, hemizygous female carriers show mosaicism for functional sweat pores, determined by a classical sweat test using starch and iodide in which the observed pattern follows the lines of Blaschko and is consistent with functional X inactivation (Traupe 1999). Mutations in the ectodysplasin-A (EDA) gene are responsible for the human disease phenotype (Monreal et al 1998), and mutations in the mouse homolog cause the tabby phenotype of hypoplastic hair, teeth, and eccrine sweat glands (Srivastava et al 1997;Grzeschik et al 2007).…”