RASopathies: Clinical Diagnosis in the First Year of Life

Abstract

Diagnosis within Noonan syndrome and related disorders (RASopathies) still presents a challenge during the first months of life, since most clinical features used to differentiate these conditions become manifest later in childhood. Here, we retrospectively reviewed the clinical records referred to the first year of life of 57 subjects with molecularly confirmed diagnosis of RASopathy, to define the early clinical features characterizing these disorders and improve our knowledge on natural history. Mildly or markedly expressed facial features were invariably present. Congenital heart defects were the clinical issue leading to medical attention in patients with Noonan syndrome and LEOPARD syndrome. Feeding difficulties and developmental motor delay represented the most recurrent features occurring in subjects with cardiofaciocutaneous syndrome and Costello syndrome. Thin hair was prevalent among SHOC2 and BRAF mutation-positive infants. Café-au-lait spots were found in patients with LS and PTPN11 mutations, while keratosis pilaris was more common in individuals with SOS1, SHOC2 and BRAF mutations. In conclusion, some characteristics can be used as hints for suspecting a RASopathy during the first months of life, and individual RASopathies may be suspected by analysis of specific clinical signs. In the first year of life, these include congenital heart defects, severity of feeding difficulties and delay of developmental milestones, hair and skin anomalies, which may help to distinguish different entities, for their subsequent molecular confirmation and appropriate clinical management.

Comprehensive massive parallel DNA sequencing strategy for the genetic diagnosis of the neuro-cardio-facio-cutaneous syndromes

“…Four of these disorders -NS, CFCS, CS and LS -share numerous similarities of phenotypic features, making the differential diagnosis challenging, particularly prenatally and in newborns. 1,5 Until now, heterozygous variants in 13 genes of this pathway (PTPN11, SOS1, RAF1, BRAF, KRAS, NRAS, HRAS, MAP2K1, MAP2K2, SHOC2, CBL, A2ML1 and RIT1) have been documented to be causally associated with NCFCS. 3,[11][12][13] Currently, because of genetic heterogeneity, only the most prevalent disease genes are assessed in routine molecular diagnosis of the NCFCS.…”

“…1,3 The diagnosis of such disorders is particularly difficult to perform in utero and in the first years of life, as most features manifest later during childhood. 4,5 Therefore, molecular analysis has become an important key for the verification of clinical diagnosis and represents a highly informative prognostic tool, with direct impact on the establishment of individual follow-up plans. 6,7 Heterozygous mutations in 11 genes associated with the RAS/MAPK signaling pathway have been causally linked to these disorders: PTPN11 (MIM 176876), SOS1 (MIM 182530), RAF1 (MIM 164760), BRAF (MIM 164757), MAP2K1 (MIM 176872), MAP2K2 (MIM601263), KRAS (MIM 190070), HRAS (MIM 190020), NRAS (MIM 164790), SHOC2 (MIM 602775) and CBL (MIM 165360).…”

Low-dose dasatinib rescues cardiac function in Noonan syndrome

“…Identifying core signaling components utilized by both NS-and NSML-related disorders could offer new insight into the progression of these diseases and potentially suggest novel therapeutic strategies to treat the more severe manifestations of NS. The identification of therapeutic approaches that can target both NS-and NSML-related cardiomyopathies as a unified therapy will provide a novel clinical utility, given the apparent challenge in diagnosis between NS and NSML, particularly within the first year of life (13,14).…”

Co‐occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death

“…To the best of our knowledge, 22 patients with NS with p.Thr42Ala have been reported in literature (Table 1). 12, 13, 15, 17, 21, 25, 26, 27, 28, 29, 30, 31, 32 However, data were limited because of the lack of a detailed description of their clinical features (Table 1). Among these reported patients with NS with p.Thr42Ala mutation in PTPN11 , ASD or atrioventricular canal defect (AVCD) were reported in six patients (Table 1).…”