SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions

Abstract

We report five cases of multiple giant cell lesions in patients with typical Noonan syndrome. Such association has frequently been referred to as Noonan-like/multiple giant cell (NL/MGCL) syndrome before the molecular definition of Noonan syndrome. Two patients show mutations in PTPN11 (p.Tyr62Asp and p.Asn308Asp) and three in SOS1 (p.Arg552Ser and p.Arg552Thr). The latter are the first SOS1 mutations reported outside PTPN11 in NL/MGCL syndrome. MGCL lesions were observed in jaws ('cherubism') and joints ('pigmented villonodular synovitis'). We show through those patients that both types of MGCL are not PTPN11-specific, but rather represent a low penetrant (or perhaps overlooked) complication of the dysregulated RAS/MAPK signaling pathway. We recommend discarding NL/MGCL syndrome from the nosology, as this presentation is neither gene-nor allele-specific of Noonan syndrome; these patients should be described as Noonan syndrome with MGCL (of the mandible, the long bone...). The term cherubism should be used only when multiple giant cell lesions occur without any other clinical and molecular evidence of Noonan syndrome, with or without mutations of the SH3BP2 gene.

Figure 1

Patient 4. (a) and (b) Facial appearance in adolescence after surgical correction of left eyelid ptosis. Characteristic gestalt of NS. The facial fullness with swollen cheeks and mild prognathism are the consequences of mandibular MGCL. (c) CT scan of the mandible with bilateral radiolucent lacunae corresponding to the extensive bilateral MGCL, more extensive on the left. (d) Partial orthopantogram of the left mandible showing the expansive lesions.

Figure 2

Patient 5. (a): Partial orthopantogram of the jaw showing cystic erosion of the mandible. (b) CT scan of the lower jaw showing bilateral cysts invading the mandibular rami.