Cognitive difficulties are argued to be common in patients with Noonan syndrome spectrum disorders (NSSDs), but findings are based on studies in which patients with variants in PTPN11 (prevalence ~50%) were overrepresented. The current study, using a structured clinical approach, describes the cognitive phenotype and psychopathology of 100 patients (aged 6 to 61 years) with nine different gene variants in the Ras/MAPK pathway underlying NSSDs (PTPN11n = 61, PTPN11 Noonan syndrome with multiple lentigines n = 3, SOS1n = 14, KRASn = 7, LZTR1n = 5, RAF1n = 4, SHOC2n = 2, CBLn = 2, SOS2n = 2). After weighted assessment and bootstrapping of the results of individual neuropsychological assessments and measures of psychopathology, cognitive performances in most variant groups were within the ranges of expectation. IQs were significantly lower in patients with variants in PTPN11, KRAS, RAF1, and SHOC2, but no specific cognitive impairments were found. The performances of younger participants (<16 years of age) did not differ from those of adults. Alexithymia and internalizing problems were more frequent in patients with variants in PTPN11 and SOS1, while PTPN11 patients also showed higher levels of externalizing problems. These results stress the need to take intelligence into account when interpreting lower cognitive performances in individual neuropsychological assessments, which is crucial for an adequate understanding and guidance of patients with NSSDs.

Dysregulation of the Ras/Mitogen-activated protein kinase (MAPK) signaling pathway is suggested to play a pivotal role in the development of the lymphatic system in patients with Noonan Syndrome (NS). Pathogenic gene variants in the Ras/MAPK pathway can therefore lead to various lymphatic diseases such as lymphedema, chylo-thorax and protein losing enteropathy. Diagnosis and treatment of the lymphatic phenotype in patients with NS remain difficult due to the variability of clinical presentation, severity and, probably, underlying unknown pathophysiologic mechanism. The objective of this article is to give an overview of the clinical presentation of lymphatic disease in relation to central conducting lymphatic anomalies (CCLA) in NS, including new diagnostic and therapeutic options. We visualized the central conducting lymphatic system using heavily T2-weighted MR imaging (T2 imaging) and Dynamic Contrast-enhanced MR Lymphangiography (DCMRL) and compared these results with the lymphatic clinical presentation in seven patients with NS. Our results show that most patients with NS and lymphatic disease have CCLA. Therefore, it is probable that CCLA is present in all patient with NS, presenting merely with lymphedema, or without sensing lymphatic symptoms at all. T2 imaging and DCMRL can be indicated when CCLA is suspected and this can help to adjust therapeutic interventions.

Noonan syndrome (NS) is a common genetic syndrome with a high variety in phenotype. Even though genetic testing is possible, NS is still a clinical diagnosis. Feeding problems are often present in infancy. We investigated the feeding status of 108 patients with clinically and genetically confirmed NS. Only patients with a documented feeding status before the age of 6 were included. A distinction was made between patients with early onset feeding problems (< 1 year) and children with late onset feeding problems (> 1 year). Seventy-one of 108 patients had feeding problems, of which 40 patients required tube feeding. Children with a genetic mutation other than PTPN11 and SOS1 had significantly more feeding problems in the first year. Fifty-two of all 108 patients experienced early onset feeding problems, of which 33 required tube feeding. A strong decrease in prevalence of feeding problems was found after the first year of life. Fifteen children developed feeding problems later in life, of which 7 required tube feeding.Conclusion: Feeding problems occur frequently in children with NS, especially in children with NS based on genetic mutations other than PTPN11 and SOS1. Feeding problems develop most often in infancy and decrease with age. What is Known:• Young children with Noonan syndrome may have transient feeding problems.• Most of them will need tube feeding. What is New:• This is the first study of feeding problems in patients with clinically and genetically proven Noonan syndrome.• Feeding problems most often develop in infancy and resolve between the age of 1 and 2.

Noonan syndrome (NS) belongs to the group of Noonan syndrome spectrum disorders (NSSD), which is a group of phenotypically related conditions. Feeding problems are often present not only in infancy but also in childhood, and even beyond that period. We describe the different aspects of feeding problems using a (theoretical) concept proposed in 2019. More than 50% of infants with NS develop feeding problems, and up to half of these infants will be tube-dependent for some time. Although, in general, there is a major improvement between the age of 1 and 2 years, with only a minority still having feeding problems after the age of 2 years, as long as the feeding problems continue, the impact on the quality of life of both NS infants and their caregivers may be significant. Feeding problems in general improve faster in children with a pathogenic PTPN11 or SOS1 variant. The mechanism of the feeding problems is complex, and may be due to medical causes (gastroesophageal reflux disease and delayed gastric emptying, cardiac disease and infections), feeding-skill dysfunction, nutritional dysfunction with increased energy demand, or primary or secondary psychosocial dysfunction. Many of the underlying mechanisms are still unknown. The treatment of the feeding problems may be a medical challenge, especially when the feeding problems are accompanied by feeding-skill dysfunction and psychosocial dysfunction. This warrants a multidisciplinary intervention including psychology, nutrition, medicine, speech language pathology and occupational therapy.

Key Clinical Message: We describe a premature hydropic infant with Noonan syndrome and a therapy refractory chylothorax. This was shown to be due to a central conducting lymphatic anomaly. After therapy with a MEK‐inhibitor the infant recovered clinically and radiologically completely, possibly by restoring lymphatic valve function.

Recent diagnostic advances reveal that lymphatic disease in Noonan syndrome (NS) and other NS-like RASopathies often stems from central conducting lymphatic anomalies (CCLAs). The RAS/MAPK-ERK pathway plays a central role in lymphangiogenesis. Targeting this pathway with MEK-inhibitor trametinib has emerged as a promising therapeutic strategy for managing CCLAs in patients with NS-like RASopathies. This case series assessed the clinical outcomes of trametinib therapy in eight patients with NS-like RASopathies and CCLA, each offering unique insights into the therapeutic efficacy of MEK inhibition. In infants, a lower dose of 0.01 mg/kg/day and earlier discontinuation of trametinib therapy effectively alleviated the symptoms of congenital chylothorax and rescued the lymphatic phenotype, compared to similar published cases. Moreover, four patients aged >11 y showed a slower response and did not achieve complete symptomatic recovery. In conclusion, it is advised to consider trametinib therapy for patients with severe, therapy-refractory CCLA in patients with NS-like RASopathies. However, individual responses to trametinib therapy may vary, with some patients demonstrating more favorable outcomes than others. Further investigation into potential enhancers and suppressors of the lymphatic phenotype is necessary for more accurate treatment predictions. While these factors are likely genetic, we cannot rule out other intrinsic or physiological factors.