The classical facial features of NS change with age [Allanson et al., 1985
]. In the newborn, typical features include tall forehead, hypertelorism, downslanting palpebral fissures, epicanthal folds, a short and broad nose with a depressed root with upturned tip, deeply grooved philtrum with high, wide peaks of the vermilion, high palate, micrognathia, low-set and posteriorly angulated ears with thick helices, and excessive nuchal skin with low posterior hairline. During infancy, the head is relatively large with a tall and prominent forehead. Hypertelorism, ptosis, or thick hooded eyelids are characteristics. The nose is short and wide with a depressed root. During childhood, the face may appear coarse or myopathic. Facial contour becomes more triangular with age, as the face lengthens. The upper face is broad while the chin is narrow and pointed. During adolescence and young adulthood, the nose has a thin, high bridge and a wide base. The neck is longer with accentuated webbing (pterygium colli) or prominent trapezius. In older adults, the nasolabial folds are prominent and the skin appears thin and transparent [Allanson et al., 1985
; Allanson, 1987
]. Features present regardless of age include blue-green irides, arched and diamond-shaped eyebrows, and low-set posteriorly angulated ears with thickened helices [Allanson, 1987
; Sharland et al., 1992
]. The hair may be wispy during infancy and curly or woolly in later childhood and adolescence.
In this study, we demonstrate that some individuals with mutations in the most commonly affected gene, PTPN11, which is correlated with the cardinal physical features, including the characteristic facial phenotype, can have a quite atypical face. There is no one alternate gestalt, and several atypical features may be found, including a broader face and coarser appearance, reminiscent of the face in CFC syndrome, which is characterized by rounder and more bulbous nasal tip with wider nasal base, and fuller lips. Other atypical faces demonstrate a long nose with low-hanging columella. Occasional individuals lack the typical wide-spaced eyes and show close-spaced features and a narrow face. At the other end of the spectrum, some individuals with KRAS mutations, which may be associated with a more severe intellectual disability with severe and longstanding feeding problems and failure to thrive, resembling Costello and CFC syndromes, can have a very typical NS facial appearance. In each gene category, as reviewed in the Methods and Results Section, both typical and unusual faces may be found.
This study was carried out before knowledge of causative mutations in SHOC2
was available. However, review of facial appearance in illustrations that are part of the supplemental information accompanying the publication of NRAS
mutations suggests that both typical and atypical facial appearance may be found in this cohort as well [Cirstea et al., 2010
]. The single recurrent SHOC2
mutation was found to be associated with a characteristic hair phenotype [Cordeddu et al., 2009
If one considers the question posed by the title: “Does phenotype predict genotype?” the answer is a clear “No.” Characteristic NS facial appearance does not point to a specific genotype. It would be most useful to know how often a particular genotype is found with an atypical face; however, it is only reasonable to expect that level of detail by studying a cohort with PTPN11 mutations as each of the other causative genes is responsible for such a small proportion of affected individuals that any one study is likely to be biased by small numbers. Such a study of PTPN11-mutation-positive individuals has not been carried out to date.
However, it may be possible to “make an educated guess” about genotype based on clues present in the face. The child with rounded features, sparse eyebrows and eyelashes, curly or sparse hair, and skin erythema may have a higher likelihood of a SOS1 mutation. Loose anagen hair makes a SHOC2 mutation more likely. Cranial or facial asymmetry may point to higher odds of a RAF1 mutation, while coarse features or a markedly prominent and wide nasal root and base may suggest a KRAS mutation. In reality, one is more likely to make a correct prediction of genotype if other factors, such as height, IQ, and type of cardiac defect are added to impressions of facial gestalt. Fortunately, with the advent of newer molecular approaches using a combination of DNA sequencing techniques to evaluate the coding regions and splice sites of all known genes, a cost-efficient testing approach does not require the physician managing the patient to predict which gene to evaluate first.