The Diverse Clinical Spectrum of Noonan Syndrome in Pediatric Endocrinology: From Classical to Atypical Phenotypes

Background/Objectives: Noonan syndrome (NS) is characterized by marked phenotypic variability. Although the classical phenotype includes short stature, craniofacial dysmorphism, skeletal abnormalities, and congenital heart defects, some patients present with subtle or atypical manifestations, making clinical recognition challenging. Methods: This retrospective case series included six pediatric patients with molecularly confirmed NS managed at the Department of Endocrinology and Metabolic Diseases, Polish Mother’s Memorial Hospital-Research Institute, Lodz, Poland. Medical records were reviewed for auxological data, phenotypic features, endocrine and skeletal assessment, cardiovascular findings, associated conditions, and multidisciplinary management. The aim of this study was to characterize the phenotypic diversity of NS in pediatric endocrine practice, with particular emphasis on growth patterns, endocrine and skeletal manifestations, and atypical clinical presentations. Results: The six patients demonstrated markedly heterogeneous clinical presentations. One boy exhibited the classical phenotype with severe short stature and pulmonary valve stenosis, whereas a girl with typical NS features maintained relatively preserved growth around the 3rd percentile. Another patient presented with progressive resorption of permanent incisor roots and a coexisting pathogenic NBN variant. A boy with LZTR1-associated NS and Klinefelter syndrome (47,XXY) demonstrated a blended phenotype and height between the 25th and 50th percentiles. Two girls lacked characteristic NS dysmorphism and presented predominantly with growth impairment, accompanied by markedly low bone mass in one case and a prolonged diagnostic pathway in the other. GH deficiency was not identified in the evaluated patients, and rhGH therapy was initiated in three patients. Conclusions: NS encompasses a broad clinical spectrum, ranging from classical phenotypes to atypical presentations dominated by growth, skeletal, or dental abnormalities. Neither the absence of characteristic dysmorphism nor relatively preserved growth excludes the diagnosis, while coexisting genetic conditions may further modify the phenotype. Awareness of this heterogeneity is essential for appropriate recognition and individualized multidisciplinary care. In selected children with otherwise unexplained growth or atypical clinical findings, consideration of NS and genetic evaluation may help establish a unifying diagnosis and potentially shorten the diagnostic pathway.