Noonan syndrome: improving recognition and diagnosis

Abstract

Noonan syndrome (NS) is a mostly dominantly inherited disorder affecting 1:1000 to 1:2500 live births. The phenotype varies in severity and can involve multiple organ systems over a patient's lifetime. Diagnosis is based on a combination of features, including typical facial features, short stature, skeletal abnormalities, presence of cardiac defects, mild developmental delay, cryptorchidism, lymphatic dysplasia and a family history of NS. The phenotype varies from oligosymptomatic adults without significant medical issues to severely affected neonates with life-threatening heart disease. Early, accurate diagnosis is important for individualised management and to optimise developmental and long-term outcomes, but mildly affected patients often go undiagnosed for both healthcare provider (HCP)-related and patient-related reasons. Lack of awareness of NS among HCPs means that some do not recognise the condition, particularly in mildly affected patients and families. Some families do not want to receive a diagnosis that medicalises a condition that may account for family traits (eg, distinctive facial features and short stature), particularly when a child's physical and cognitive development may be satisfactory. As for any condition with lifelong effects on multiple organ systems, a multidisciplinary approach provides the best care. It is proposed that increasing awareness of NS among non-specialist HCPs and other professionals could help direct a parent/carer to seek specialist advice and increase the number of NS diagnoses, with the potential to optimise lifelong patient outcomes. Non-specialists do not need to become experts in either diagnosis or treatment; however, early recognition of NS and referral to an appropriate specialist is important.

Keywords: endocrinology; genetics; syndrome.

Figure 1

Features of Noonan syndrome (NS).

Figure 2

The RAS–MAPK signalling pathway showing mutations that may lead to diseases such as Noonan syndrome (reproduced with permission from Zenker, 2020). Some of the pathway components exist in multiple isoforms (eg, RAS: KRAS, HRAS, NRAS, RRAS; RAF: RAF1, BRAF; SOS: SOS1, SOS2, etc). ^aAlso known as Noonan syndrome with multiple lentigines. CFC, cardiofaciocutaneous; MAPK, mitogen-activated protein kinase; P, proline; RTK, receptor tyrosine kinase enzyme; Ub, ubiquitin.

Figure 3

The face of Noonan syndrome over time. Public domain images from the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.