Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

Abstract

Summary Background Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. Objectives To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype–genotype correlations with or without the presence of PTPN11 mutations. Methods We performed a large 4‐year, prospective, multicentric, collaborative dermatological and genetic study. Results Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11‐NS, 34 patients with PTPN11‐NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11‐NS, present in 53·8% of patients. Multiple lentigines and café‐au‐lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. Conclusions The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.

Low-Grade Gliomas in Patients with Noonan Syndrome: Case-Based Review of the Literature

“…Although our patient had low-grade gliomas, the peculiarity of our case is that she developed three different types of brain tumors at the same time, without any hematological disease. Another particular feature of our patient is that she had a positive genetic test for NS and, at the same time, she developed phenotypic characteristics also present in NF1, such as café-au-lait spots see [ 21 ], lentigines, in association with an optical-diencephalic lesion, although phenotypic overlapping is not uncommon for patients affected with RASopathies [ 22 , 23 ]. Nevertheless, the case was negative on clinical exome sequencing including NF1, but though she could have an undetected mutation that does not affect the coding part of the gene.…”

Juvenile xanthogranuloma in Noonan syndrome

“…Cutaneous findings in NF1 set it apart from other RASopathies in that clinical diagnostic criteria are based on multiple café au lait macules, intertriginous freckling and neurofibromas (Boyd et al, 2009). In contrast, cutaneous findings in NS are non‐specific (Bessis et al, 2019). Juvenile xanthogranuloma (JXG) is a cutaneous finding that has been associated with NF1.…”

NRAS associated RASopathy and embryonal rhabdomyosarcoma

“…Common manifestations of Noonan syndrome include short stature, congenital heart disease, risk for hypertrophic cardiomyopathy, lymphatic abnormalities that may result in a webbed neck, pectus anomaly, early developmental delay, characteristic facial features, and risk for mild intellectual disability and/or learning disability. Some patients with Noonan syndrome have numerous nevi or lentigines and there does appear to be some genotype-phenotype correlation to this (Bessis et al, 2019). Individuals with Noonan syndrome do have an increased risk for certain malignancies, primarily juvenile myelomonocytic leukemia.…”