Gorlin Lecture

Genetic Disorders Involving the Oral and Maxillofacial Region: A Dermatologist’s View

Speaker: Rudolph Happle, MD

* This speaker has been verified as having no relevant conflicts of interest or financial relationships to disclose.

Course Description (2 Credit Hours)

In 1964, Robert Gorlin published his well-known book “Syndromes of the Head and Neck”. Remarkably, in his hands the next editions grew out to include genetic anomalies of the entire human body. This shows that examination of the maxillofacial and oral region plays a crucial role in syndrome recognition.

In the first part of this lecture, maxillofacial and oral lesions of autosomal dominant syndromes (neurofibromatosis 1, tuberous sclerosis, Gorlin syndrome), autosomal recessive traits (xeroderma pigmentosum, Papillon-Lefèvre syndrome), and X-linked Christ-Siemens-Touraine syndrome are considered.  The second part of the lecture deals with segmental mosaicism. The skin is easily accessible to recognize such phenotypes. The concept of lethal mutations surviving as mosaics has been proven at the molecular level in many sporadically occurring traits such as Schimmelpenning syndrome and encephalocraniocutaneous lipomatosis.  In the group of autosomal dominant skin disorders, the well-known type 1 segmental mosaicism is noted in neurofibromatosis 1, tuberous sclerosis, Apert syndrome, and Gorlin syndrome. The less well known type 2 segmental mosaicism originates in a heterozygous embryo from a postzygotic event of loss of heterozygosity, resulting in a pronounced segmental involvement being superimposed on the ordinary non-segmental phenotype.  Molecular proof of this concept has been provided in numerous traits including neurofibromatosis 1 and Gorlin syndrome. In the category of epigenetic mosaicism, a linear pattern of lyonization is noted in Goltz syndrome and Conradi-Hünermann-Happle syndrome.  Finally, possible examples of superimposed segmental manifestation of polygenic traits include lupus erythematosus, dematomyositis, and pemphigus vulgaris.

Objectives of Course:

  1. To make pathologists familiar with monogenic disorders involving the maxillofacial and oral region and, in particular, with the facial cutaneous and oral manifestations of segmental mosaicism that can today be investigated at the molecular level.  These advances help the understanding of the different forms of mosaic disorders such as lethal autosomal mutations surviving as segmental mosaics
  2. Be able to distinguish the simple type 1 segmental mosaicism of autosomal dominant genodermatoses from the type 2 segmental mosaicism, which is important for the purpose of correct genetic counseling
  3. Have an understanding why the Lyon effect of X inactivation is a particular form of epigenetic mosaicism, and why an analogous effect of monoallelic expression may also involve autosomal gene loci
  4. Understand why in common skin disorders with a polygenic (“complex”) background, the “n+1” rule may explain a pronounced mosaic manifestation being superimposed on a less conspicuous, non-segmental involvement, although molecular proof of principle is still lacking.

At the end of the course the participant will:

  • Be familiar with monogenic disorders involving the maxillofacial and oral region, in particular, with the facial cutaneous and oral manifestations of segmental mosaicism that can today be investigated at the molecular level. These advances help the understanding of the different forms of mosaic disorders such as lethal autosomal mutations surviving as segmental mosaics
  • Be able to distinguish the simple type 1 segmental mosaicism of autosomal dominant genodermatoses from the type 2 segmental mosaicism, which is important for the purpose of correct genetic counseling
  • Have a better understanding of why the Lyon effect of X inactivation is a particular form of epigenetic mosaicism, and why an analogous effect of monoallelic expression may also involve autosomal gene loci
  • Understand why in common skin disorders with a polygenic (“complex”) background, the “n+1” rule may explain a pronounced mosaic manifestation being superimposed on a less conspicuous, non-segmental involvement, although molecular proof of principle is still lacking.