A postzygotic activating AKT1 mutation in a discordant monozygotic twin with Proteus syndrome

Background: Proteus syndrome is a rare, complex disorder characterized by asymmetric overgrowth of body parts including connective tissue nevi, epidermal nevus, and vascular malformations. Clinical diagnostic criteria comprise mosaic distribution, sporadic occurrence, and progressive course.

Patients and Methods: We observed Proteus syndrome in discordant monozygotic twins [1]. The affected 13-year-old boy showed progressive overgrowth of his right leg, in particular of single toes, and a small cerebriform connective tissue nevus on his right fourth toe. A PCR-amplified short tandem repeat analysis showed concordance of all alleles in both twins. These twins were included in a research project aiming to elucidate the molecular basis of Proteus syndrome [2]. Results of exome sequencing of DNA from lesional biopsies were compared with DNA from unaffected tissue obtained from the same patients.

Results: A postzygotic activating mutation (c.49G→A, p.Glu17Lys) within the oncogene AKT1, encoding the AKT1 kinase, was detected in lesional tissue of patients with Proteus syndrome, but not in samples of healthy tissue. The same postzygotic mutation was found in lesional samples of the twin with Proteus syndrome, but not in his healthy twin brother.

Conclusion: The molecular proof of discordance for Proteus syndrome in a monozygotic twin pair illustrates in a convincing way the hypothesis, as proposed 25 years ago [3], that the disorder is caused by a lethal mutation surviving by mosaicism.

Literature:

Brockmann K, Happle R, Oeffner F, König A: Monozygotic twins discordant for Proteus syndrome. Am J Med Genet 2008;146A:2122–5.

Lindhurst MJ, Sapp JC, Teer JK et al: A mosaic activating mutation AKT1 associated with the Proteus syndrome. N Engl J Med 2011;365:611–9.

Happle R: Cutaneous manifestation of lethal genes. Hum Genet 1986;72:280.