The McCune-Albright syndrome: molecular diagnostic methods

The McCune-Albright syndrome (MAS) is a rare congenital disorder hallmarked by the clinical triad of endocrinopathies, café-au-lait pigmented skin lesions, and fibrous dysplasia of bone. In according to the variable involvement of tissues following the lines of the embryologic development, the disease was proposed to derive from postzygotic genetic defect, leading to a mosaic distribution of mutated cells. MAS derives from missense, gain-of-function mutations that occur commonly at the Arg201 residue in GNAS locus, determining the constitutional activation of the alpha subunit of stimulatory G protein, resulting in impaired cellular proliferation and function of affected tissues. Commonly the diagnosis is performed clinically, but the clinical features occur too late, leading to an important delay for management of complications. For this reason, a reliable molecular method would be useful for the early diagnosis of this condition, and it would allow prompt therapeutic management and, overall, the optimization of the quality of life. The main issue is the mosaic state of MAS, which makes the molecular diagnosis highly challenging. Particularly, biological samples such as peripheral blood, that would be easily accessible for mutation detection test, bear a low level of mosaicism, leading to high rates of false negative results. To overcome the underestimation of mosaic variants, different molecular techniques had been developed over the years. In particular, three methods (PNA-NGS method, COLD-MAMA PCR, digital PCR) have reached higher sensitivity and accuracy in comparison with traditional diagnostic techniques, normally used for Mendelian disorders’ diagnosis, which are not functional for detection of MAS. Specifically, dPCR shows many advantages in sensitivity, detection limit, cost, and time, leading to an accurate GNAS mutations detection.