The face of Noonan syndrome: Does phenotype predict genotype

Abstract

The facial photographs of 81 individuals with Noonan syndrome, from infancy to adulthood, have been evaluated by two dysmorphologists (JA and MZ), each of whom has considerable experience with disorders of the Ras/MAPK pathway. Thirty-two of this cohort have PTPN11 mutations, 21 SOS1 mutations, 11 RAF1 mutations, and 17 KRAS mutations. The facial appearance of each person was judged to be typical of Noonan syndrome or atypical. In each gene category both typical and unusual faces were found. We determined that some individuals with mutations in the most commonly affected gene, PTPN11, which is correlated with the cardinal physical features, may have a quite atypical face. Conversely, some individuals with KRAS mutations, which may be associated with a less characteristic intellectual phenotype and a resemblance to Costello and cardio-facio-cutaneous syndromes, can have a very typical face. Thus, the facial phenotype, alone, is insufficient to predict the genotype, but certain facial features may facilitate an educated guess in some cases.

FIG. 1

Individuals with PTPN11 mutations, from infancy to adolescence, and a typical face of Noonan syndrome.

FIG. 2

PTPN11 mutations and a facial gestalt uncharacteristic of Noonan syndrome.

FIG. 3

Individuals with SOS1 mutations and a coarse appearance, which, in infancy, can resemble the face of Costello syndrome (A,B). Reproduced from Zenker et al. [2007b] with permission from BMJ Publishing Group Ltd.

FIG. 4

Very typical features of Noonan syndrome, seen from early childhood to adulthood, in individuals with SOS1 mutations.

FIG. 5

Brothers with a RAF1 mutation and essentially unremarkable facial features.

FIG. 6

Typical facial features of Noonan syndrome in four children of varying ages, each with a RAF1 mutation.

FIG. 7

RAF1 mutations and cranial asymmetry, a long narrow nose, and markedly downslanting palpebral fissures.

FIG. 8

KRAS mutations associated with typical facies of Noonan syndrome. Reproduced from Zenker et al. [2007a] with permission from BMJ Publishing Group Ltd.

FIG. 9

KRAS mutations and unusual facial features: in childhood a coarseness suggestive of Costello syndrome; in adulthood a broadening of features with marked widespacing of eyes and broad nasal root and tip somewhat reminiscent of G/BBB and Teebi hypertelorism syndromes. Reproduced from Zenker et al. [2007a] with permission from BMJ Publishing Group Ltd.