ENOrphanet Journal of Rare Diseases | Study on the Prevalence, Management, and Quality of Life Impact of Lower Limb Segmental Overgrowth in NF1 Patients
Date: February 12, 2026
Classification: Frontiers
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This study presents the first systematic assessment of the epidemiological characteristics, treatment strategies, and quality of life impact of lower limb segmental overgrowth (SOLL) in patients with neurofibromatosis type 1 (NF1). Using the GOAL-LD scale, it reveals significant functional and psychological burdens persisting even after surgical intervention, highlighting the importance of individualized multidisciplinary management.
Literature Overview
The article 'Prevalence and management of lower limb segmental overgrowth in patients with NF1: an observational study,' published in the Orphanet Journal of Rare Diseases, reviews and summarizes the clinical features, treatment approaches, and long-term outcomes of seven cases of lower limb segmental overgrowth (SOLL) identified among 553 pediatric NF1 patients. Through retrospective analysis, the study evaluates the prevalence of limb length discrepancy (LLD) associated with SOLL, management strategies, and health-related quality of life, using the GOAL-LD questionnaire to quantify patient-reported outcomes. Results indicate a 1.3% prevalence of SOLL in NF1, with most patients having ipsilateral plexiform neurofibromas. Despite surgical treatment, quality of life remains significantly impaired, underscoring the need for early recognition and comprehensive intervention. The study also explores potential pathological mechanisms, including similarities to overgrowth syndromes linked to the PI3K/AKT pathway and the therapeutic potential of the MEK inhibitor selumetinib. This work provides critical clinical evidence on the natural history of the rare complication SOLL and emphasizes the necessity of structured follow-up and individualized treatment.Background Knowledge
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused by mutations in the NF1 gene located at 17q11.2, leading to loss of neurofibromin function and subsequent activation of the RAS/MAPK and PI3K/AKT signaling pathways, affecting cell proliferation, differentiation, and survival. Clinical manifestations of NF1 are highly heterogeneous, with typical features including café-au-lait spots, axillary freckling, Lisch nodules, neurofibromas, and skeletal abnormalities. Skeletal involvement, such as scoliosis and tibial pseudarthrosis, is relatively common, whereas lower limb segmental overgrowth (SOLL) is extremely rare and often overlooked. SOLL manifests as focal overgrowth of soft and bone tissues in one limb, leading to progressive limb length discrepancy (LLD), which can severely affect gait, posture, and psychosocial functioning. The pathogenesis of SOLL is not yet fully understood and may be related to growth factors secreted by localized plexiform neurofibromas (PN) or somatic 'second-hit' mutations, similar to PIK3CA-related overgrowth spectrum (PROS). However, whether NF1-related SOLL should be classified as a distinct entity remains controversial. Clinical management is challenging: conservative treatments such as shoe lifts are suitable for mild LLD, while severe cases require surgical interventions like epiphysiodesis or limb lengthening. However, due to complex bony deformities and neurofibroma infiltration commonly seen in NF1 patients, surgical risks are high and outcomes uncertain. Additionally, the lack of NF1-SOLL-specific quality-of-life assessment tools has led previous studies to rely heavily on radiological parameters, neglecting patient-reported outcomes. This study introduces the GOAL-LD scale, enabling the first systematic evaluation of functional status and psychological burden in NF1-SOLL patients, filling a critical evidence gap. Furthermore, with the successful use of MEK inhibitors like selumetinib in PN treatment, early intervention in SOLL to halt overgrowth progression has emerged as a promising research direction. Thus, this study not only provides epidemiological data but also lays the foundation for future mechanistic exploration and treatment optimization.
Methods and Experiments
The research team conducted a retrospective analysis of clinical data from 553 pediatric NF1 patients followed between 1992 and 2024 at the pediatric NF1 referral center of the 'Luigi Vanvitelli' University in Italy. Inclusion criteria were NF1 diagnosis confirmed by NIH and Legius criteria with associated SOLL. SOLL was defined as focal overgrowth of soft tissue or bone in the lower limb, confirmed by comparing mid-thigh and mid-calf girths bilaterally. Limb length discrepancy (LLD) was assessed clinically and via full-length limb radiographs, which had to meet specific standards (e.g., limb extended, femoral head and ankle visible on the same image). Data collected included demographics, skeletal deformities (e.g., genu valgum, scoliosis), presence and location of PN, and LLD measurements at initial diagnosis, maximum discrepancy, time of surgery, and last follow-up. All enrolled patients or their guardians completed the GOAL-LD quality-of-life questionnaire, covering seven domains: gait function, pain and fatigue, activity participation, gait appearance, orthosis use, body image, and self-esteem. Data were analyzed using descriptive statistics.Key Findings and Insights
Significance and Outlook
This study is the first observational investigation specifically focused on SOLL in NF1 patients, providing baseline epidemiological data for this rare complication and correcting previous underestimations. By systematically capturing dynamic LLD changes and treatment responses, it offers real-world evidence for clinical decision-making. More importantly, the introduction of the GOAL-LD scale enables patient-centered outcomes, revealing that even after anatomical correction, significant psychosocial burdens persist, suggesting the need for integrated rehabilitation, psychological support, and multidisciplinary collaboration.
The findings suggest SOLL may be closely linked to local PN activity, raising the question of whether MEK inhibitors like selumetinib could halt overgrowth during a pre-symptomatic phase—an avenue worth exploring. Future studies should include prospective cohorts combining radiomics and molecular testing to identify high-risk individuals and assess the feasibility of early pharmacological intervention. Additionally, establishing an international NF1-SOLL registry will help accumulate larger datasets to develop more precise predictive models and treatment guidelines.
Conclusion
This study systematically evaluates the clinical characteristics and management of lower limb segmental overgrowth (SOLL) in patients with neurofibromatosis type 1 (NF1), revealing a prevalence of 1.3% in the pediatric NF1 population. SOLL is frequently associated with ipsilateral plexiform neurofibromas, leading to significant limb length discrepancy (LLD) that severely impacts quality of life. Despite most patients undergoing surgical treatment, GOAL-LD questionnaires indicate major challenges in gait appearance, body image, and orthosis use, demonstrating that anatomical correction does not necessarily translate into functional or psychological benefits. The study emphasizes that SOLL is a complex, multisystem disorder requiring individualized, multidisciplinary management. Early recognition of LLD progression is crucial, potentially offering a time window for non-surgical interventions such as MEK inhibitors. Current treatments are largely reactive rather than preventive, highlighting gaps in understanding the disease's natural history. Future efforts should include multicenter prospective studies to explore the molecular mechanisms of SOLL, evaluate the potential of early targeted therapies, and establish standardized follow-up and intervention pathways to truly improve long-term outcomes and quality of life for NF1 patients. This work sets a patient-centered benchmark for clinical research into rare complications.
