Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.

Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.

[Control of postoperative pain in children undergoing hypospadias surgery: quasi-experimental controlled trial]. / Controllo del dolore post-operatorio nel bambino operato di ipospadia: studio quasi-sperimentale controllato.

BACKGROUND: Hypospadias is one of the most common congenital anomalies occurring in approximately (1/300) male births. If it is not surgically corrected the consequences may negatively impact on quality of life in adolescents. The surgery is very invasive and the post-operative phase very painful. To improve the control of post-operative pain, continuous analgesia via epidural catheter was implemented. AIMS: To compare the effectiveness in controlling pain of two different regimens: continuous epidural catheter infusion vs oral and rectal non-steroidal pain-killers. MATERIALS AND METHODS: Comparative study on children undergoing hypospadias surgery. Group A (catheter) was treated with continuous postoperative analgesia via epidural catheter and Group B (scheduled times) with rectal and oral analgesics at scheduled times and on demand, after caudal block. In both groups nurses measured pain with VAS and FLACC scales (score from 0 to 10) for 72 hours after surgery. RESULTS: 41 children were studied (average age 64.1 months, SD 47.3), with 332 post-operative pain recordings (Group A n = 161, Group B n = 171). Mean pain score of Group A was 0.13 (SD 0.3) and 0.45 (SD 0.8) in group B, p = 0.006. The median duration of the epidural catheter was 65 hours, mean 51.8 hours (SD 24.3). During the 1st post-operative medication, the mean pain score in Group A was 1.2 (SD 1.4), and 3.2 (SD 1.8) in group B, p = 0.003. In group A the number of pain scores indicating pain (> 0) where 3.1% while in group B were 10.5%, p = 0.0007. CONCLUSIONS: In children undergoing hypospadias surgery, post-operative analgesia with continuous epidural catheter infusion seems to offer a better analgesic coverage than the traditional oral/rectal analgesic treatment at scheduled times and on demand.

Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome.

Activating mutations in v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been identified as the molecular cause underlying Costello syndrome (CS). To further investigate the phenotypic spectrum associated with germline HRAS mutations and characterize their molecular diversity, subjects with a diagnosis of CS (N = 9), Noonan syndrome (NS; N = 36), cardiofaciocutaneous syndrome (CFCS; N = 4), or with a phenotype suggestive of these conditions but without a definitive diagnosis (N = 12) were screened for the entire coding sequence of the gene. A de novo heterozygous HRAS change was detected in all the subjects diagnosed with CS, while no lesion was observed with any of the other phenotypes. While eight cases shared the recurrent c.34G>A change, a novel c.436G>A transition was observed in one individual. The latter affected residue, p.Ala146, which contributes to guanosine triphosphate (GTP)/guanosine diphosphate (GDP) binding, defining a novel class of activating HRAS lesions that perturb development. Clinical characterization indicated that p.Gly12Ser was associated with a homogeneous phenotype. By analyzing the genomic region flanking the HRAS mutations, we traced the parental origin of lesions in nine informative families and demonstrated that de novo mutations were inherited from the father in all cases. We noted an advanced age at conception in unaffected fathers transmitting the mutation.

NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome.

Neurofibromatosis type 1 (NF1) demonstrates phenotypic overlap with Noonan syndrome (NS) in some patients, which results in the so-called neurofibromatosis-Noonan syndrome (NFNS). From a genetic point of view, NFNS is a poorly understood condition, and controversy remains as to whether it represents a variable manifestation of either NF1 or NS or is a distinct clinical entity. To answer this question, we screened a cohort with clinically well-characterized NFNS for mutations in the entire coding sequence of the NF1 and PTPN11 genes. Heterozygous NF1 defects were identified in 16 of the 17 unrelated subjects included in the study, which provides evidence that mutations in NF1 represent the major molecular event underlying this condition. Lesions included nonsense mutations, out-of-frame deletions, missense changes, small inframe deletions, and one large multiexon deletion. Remarkably, a high prevalence of inframe defects affecting exons 24 and 25, which encode a portion of the GAP-related domain of the protein, was observed. On the other hand, no defect in PTPN11 was observed, and no lesion affecting exons 11-27 of the NF1 gene was identified in 100 PTPN11 mutation-negative subjects with NS, which provides further evidence that NFNS and NS are genetically distinct disorders. These results support the view that NFNS represents a variant of NF1 and is caused by mutations of the NF1 gene, some of which have been demonstrated to cause classic NF1 in other individuals.