INTRODUCTION
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome that affects multiple organs, including the skin, brain, heart, kidneys, and lungs, caused by defects in the TSC1/TSC2 complex, which inhibits the mammalian target of rapamycin (mTOR) pathway[1]. The incidence of TSC is approximately 1 in 6000 to 1 in 10000, with a mean age of onset of around 7.5 years. TSC primarily affects children[2-4]. In affected children, mutations in the tumor suppressor genes TSC1 or TSC2 on chromosome 9q34 and 16p13.3 activate the mTOR pathway, leading to abnormal cell proliferation and the formation of misshapen tumors in multiple organs[5,6].
Given that TSC disrupts the cellular structure of multiple organs, its clinical phenotype is diverse. TSC can cause multisystem damage to the skin, heart, nerves, kidneys and other organs and systems. In children, the disease often begins with epileptic symptoms, and 90% of children experience seizures during their lifetime[7]. The diagnosis of TSC is challenging, as previous diagnostic criteria include multiple characteristic clinical changes, which are difficult to recognize. According to the new diagnostic criteria, genetic detection of a pathogenic mutation in the TSC1 or TSC2 genes is significant for the diagnosis of TSC regardless of the presence or absence of clinical manifestations, constituting an independent diagnostic criterion[8]. Treatment primarily focuses on managing symptoms caused by the misshapen tumors and taking preventive measures to avoid loss of function in the affected organs. Traditional treatment of TSC mainly involves surgery and symptomatic support. In recent years, the treatment of TSC has also emphasized the use of molecularly targeted drugs[9]. TSC is a systemic disease; therefore, multidisciplinary follow-up is necessary if multiple organs or tissues are involved. This requires evaluation and follow-up with teams from genetics, neurology, ophthalmology, nephrology, and dentistry, among others.
Lymphedema (LE) is characterized by interstitial edema and protein accumulation due to defective lymphatic drainage. LE can be categorized into two groups: (1) Primary LE (PLE); and (2) Secondary LE. The incidence of PLE is approximately 1 in 10000, with a female to male ratio of 3.5:1. Depending on the age of onset, PLE is classified into three forms: (1) Congenital; (2) Early-onset; and (3) Late-onset[10,11].
Both TSC and PLE are rare diseases, and the probability of their simultaneous occurrence is low. According to current reports, only a dozen cases have been reported internationally. However, there may be correlations between the simultaneous occurrence of these two diseases, providing new ideas for studying the pathogenic mechanism of TSC and PLE.
HIGHLIGHT AND COMMENT
In the May 26th issue of the World Journal of Clinical Cases, Li et al[12] reported a case of TSC-PLE, retrospectively analyzing the clinical features, imaging, diagnosis and management of a 16-year-old male patient with right lower extremity swelling. The diagnosis of TSC-PLE was successfully confirmed in this patient using advanced imaging methods combined with molecular genetic testing techniques. There are few previous reports on the imaging evaluation of this condition. Therefore, the assessment of the degree of lymphatic dysplasia in this case, along with the collection of imaging evidence for TSC, will contribute to the understanding of TSC-PLE.
It is worth noting that, in some cases, congenital edema is the only external manifestation in children with TSC. The diagnosis of TSC may be particularly difficult in such cases as skin lesions are often difficult to visualize in newborns and, lesions in other tissues are more subtle[13,14]. The initial diagnosis of PLE can be made by ultrasonography and physical examination after birth. The analysis of new cases of TSC-PLE can provide guidance for accurate prenatal diagnosis of fetuses with LE in combination with manifestations of TSC, as well as early diagnosis and tailored therapeutic strategies to improve prognosis. For patients diagnosed with PLE, TSC screening can be routinely performed, such as mTOR immunohistochemistry of pathological tissue biopsies and genetic evaluation of blood samples. Genetic testing of children with congenital LE at birth or even prenatally can help to identify the presence of genetic disorders and thus select treatment options.
With the emergence of precision medicine, the treatment of TSC-PLE is progressively emphasizing molecularly targeted therapies. Targeted therapy with rapamycin, a potent and specific mTOR inhibitor, has been used[15-18]. Rapamycin effectively relieves TSC-related symptoms and can be combined with surgery to reduce the size of lymphatic malformations and stabilize the growth of lymphatic vessels. Among mTOR inhibitors, everolimus is also often a drug of choice. Symptomatic treatments, such as liposuction and volume reduction for LE, can be chosen on the basis of targeted therapy. Antiepileptic drugs are also used in early epileptic episodes to mitigate the damage to growth and development. In this group of children, the use of appropriate medication should be initiated when abnormal epileptic waves appear on the electroencephalography, even in the absence of clinical manifestations[10,15].
Li et al[12] reviewed the literature of 16 previously reported cases of TSC-PLE, and found that there may be a gender predisposition for onset. They summarized all the reported cases, and recorded in detail the clinical manifestations of the patients, the mutated genes, and the corresponding treatments for different cases in a tabular format.
LIMITATION
From the summary of the data, it appears that females with TSC are more frequently affected by LE than male patients; a phenomenon that Li et al[12] speculate may be related to estrogen concentration[19]. Patients carrying the TSC2 causative gene are also more likely to develop LE than those carrying the TSC1 causative gene. The mechanisms behind these observations are still unclear and need further exploration. Selection bias may also exist due to the small number of cases. Further studies with large numbers of PLE-TSC patients are needed to minimize selection bias.
This study was limited by its retrospective design and small sample size, and the pathophysiological mechanisms leading to the development of LE are currently unknown due to the lack of clinical details and the lack of testing in some patients. It is currently believed that mutations in the TSC gene lead to activation of the mTOR pathway, but the specific relationship between mTOR and the formation and growth of lymphatic vessels still needs to be investigated.
Some studies have found that mTOR inhibitors can improve LE in some patients with TSC-PLE, but there is no significant change in the presence of lymphatic vessel malformations[11,20]. In some patients, the size and extent of LE remained unchanged, with no significant improvement or deterioration after drug treatment. Therefore, defining the therapeutic range of mTOR inhibitors such as rapamycin used in the treatment regimen and the systematic assessment of the therapeutic outcome remain areas for further investigation. The conjecture that rapamycin may inhibit lymphangiogenesis by downregulating vascular endothelial growth factor expression in p-mTOR-negative cases also lacks confirmation in prospective randomized trials. Data on the safety, efficacy, and the prognosis of mTOR inhibitors in treating infants and children with TSC-PLE are limited, leading to an inability to predict adverse events with prolonged medication use and long-term safety under maintenance therapy. Further investigation is needed to select early drug treatment measures and evaluate preventive efficacy in children with TSC-PLE.
CONCLUSION
The case report of TSC-PLE enhances clinical understanding of this rare disease and underscores the importance of identifying children with PLE in the context of TSC. While improving the early diagnosis of children, it is important to raise awareness of the various manifestations of this disease. The study of the pathophysiological mechanisms and therapeutic options is essential to improve diagnostic strategies and therapeutic interventions for patients with TSC-PLE. In this context, the need for tailored therapeutic strategies is also emphasized, allowing individualized symptomatic treatment and relief while targeting children with different clinical presentations.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Medicine, research and experimental
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade B
P-Reviewer: Haydar H S-Editor: Luo ML L-Editor: A P-Editor: Zhang XD
