Tuberous sclerosis complex combined with primary lymphedema: A case report

Abstract

BACKGROUND

Tuberous sclerosis complex (TSC) and primary lymphedema (PLE) are both rare diseases, and it is even rarer for both to occur in the same patient. In this work, we have provided a detailed description of a patient's clinical presentation, imaging findings, and treatment. And a retrospective analysis was conducted on 14 published relevant case reports.

CASE SUMMARY

A 16-year-old male came to our hospital for treatment due to right lower limb swelling. This swelling is already present from birth. The patient’s memory had been progressively declining. Seizures had occurred 1 year prior at an unknown frequency. The patient was diagnosed with TSC combined with PLE through multimodal imaging examination: Computed tomography, magnetic resonance imaging, and lymphoscintigraphy. The patient underwent liposuction. The swelling of the patient's right lower limb significantly improved after surgery. Epilepsy did not occur.after taking antiepileptic drugs and sirolimus.

CONCLUSION

TSC with PLE is a rare and systemic disease. Imaging can detect lesions of this disease, which are important for diagnosis and treatment.

Key Words: Tuberous sclerosis complex, Lymphedema, Sirolimus, Multimodal imaging examination, Case report

Core Tip: Tuberous sclerosis complex with primary lymphedema (TSC-PLE) is a rare, congenital and systemic disease closely related to gene mutations. The clinical manifestations of TSC-PLE are diverse. Multiple imaging methods can detect systemic organ and tissue lesions, which are important for clinical diagnosis and treatment. Rapamycin-targeted therapy is the main treatment for this disease and can simultaneously treat the symptoms of both TSC and PLE. Liposuction can effectively improve limb swelling in patients. This case is the 17^th patient with TSC-PLE worldwide. And this case has comprehensive clinical, imaging, genetic testing and treatment.

INTRODUCTION

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic diseases characterized by multiple organ lesions and closely related to the TSC gene[1-3]. Lymphedema (LE) is the accumulation of protein rich lymphatic fluid in subcutaneous interstitial tissue, irreversible fibrosis of adipose tissue, and ultimately causing limb swelling. LE can be divided into primary LE (PLE) and secondary LE based on its etiology[4]. TSC and PLE are rare diseases, and it is even rarer for both to occur in the same patient. In this work, we aimed to intended to increase awareness of TSC and PLE by reporting a case and reviewing the relevant literature.

CASE PRESENTATION

Chief complaints

A 16-year-old male came to our hospital for treatment due to right lower limb swelling. This swelling is already present from birth without any obvious cause or reason. It worsened after activity and improved after rest.

History of present illness

Ten years prior, there had been swelling of the right scrotum and fluid accumulation in the right testicular sheath. Seven years prior, the patient had broken out with erysipelas. In recent years, the patient’s memory had been progressively declining. Seizures had occurred 1 year prior at an unknown frequency but improved after treatment with antiepileptic medication.

Physical examination

The skin became red and thick and exhibited poor elasticity, high temperature, and visible pigmentation. Restricted movement of joints was observed in the right lower limb.

Laboratory examinations

Genetic testing revealed a mutation in the TSC2 gene. The heterozygous mutation of nucleotide number 2251 from cytosine C to thymine T (c.2251C>T) resulted in a mutation of amino acid number 751 from arginine to terminator (p.ARG751Ter). The patient's parents did not exhibit any TSC gene abnormalities.

Imaging examinations

A computed tomography (CT) scan of the head revealed symmetrically distributed calcified nodules located beneath the ependymal membrane of both lateral ventricles (Figure 1A). An abdominal enhanced CT scan showed multiple, regular and well-defined nodules in both kidneys. The internal density of the nodule was uneven, with visible fat density and soft tissue density (Figure 1B). A chest CT scan showed multiple ground glass opacities in both lungs, mainly distributed under the pleura, with a diameter of 3-10 mm. However, no pulmonary cysts were found in either lung (Figure 1C). In addition, ⁹⁹Tc^m-DX-lymphoscintigraphy revealed thickening of the right lower limb, but lymphatic vessels in the right lower limb were not visualized. The right inguinal, iliac, and lumbar lymphatic vessels and lymph nodes were not visualized, and the imaging agent was diffusely and unevenly distributed in the right lower limb, waist, buttocks, and external genital area (Figure 2). The short time inversion recovery sequence of the lower limb magnetic resonance imaging (MRI) showed thickening of the skin and swelling of subcutaneous soft tissue in the right lower limb, with honeycomb, crescent, and band signs visible inside. Thickened, tortuous, and dilated veins were also observed (Figures 3 and 4).

Figure 1 Computed tomography scan. A: Computed tomography (CT) scan of the head. Calcified nodules located beneath the ependymal membrane of both lateral ventricles; symmetrically distributed (orange arrow); B: Abdominal CT enhancement. Multiple regular and well-defined nodules in both kidneys, with visible fat density inside. After enhancement, the solid components are enhanced, but the fat components are not enhanced (orange arrow); C: Chest CT scan. An irregular ground glass opacity nodule in the posterior basal segment of the right lower lobe of the lung (orange arrow).

Figure 2 ⁹⁹Tc^m-DX-lymphoscintigraphy: The imaging agent was diffusely and unevenly distributed in the right lower limb, waist, buttocks, and external genital area (orange arrow). The lymphatic vessels in the right lower limb were not visualized, and the right inguinal, iliac, and lumbar lymphatic vessels and lymph nodes were not visualized (orange dashed arrow).

Figure 3 Coronal view of the short time inversion recovery sequence of the entire lower limb. Compared with those on the left, the skin on the right lower limb was thickened, and the subcutaneous soft tissue was swollen, with abnormally high signal shadows visible inside (orange arrows).

Figure 4 Short time inversion recovery sequence transverse section of lower limb magnetic resonance imaging: Signs of lymphedema in subcutaneous soft tissue, including the honeycomb sign (white arrow) and band sign (white dashed arrow). Thickened, tortuous and dilated veins were observed (orange arrow).

FINAL DIAGNOSIS

Based on comprehensive clinical, imaging, and genetic testing, the male patient was diagnosed with TSC combined with PLE.

TREATMENT

The patient was prescribed oral oxcarbazepine and sodium valproate to suppress seizures and sirolimus to treat the TSC. The patient underwent liposuction and volume reduction surgery to reduce lower limb edema.

OUTCOME AND FOLLOW-UP

Prognosis: The swelling of the patient's right lower limb significantly improved after surgery, and the morphology improved well. Epilepsy did not occur.

DISCUSSION

TSC is an autosomal dominant genetic disorder characterized by lesions in multiple organs. TSC1 or TSC2 gene mutations can lead to structural activation of the mechanical target of rapamycin pathway, dysregulation of cell proliferation, and obstruction of lymphangiogenesis. The incidence rate is approximately 1/6000-10000; these tumours can be familial or sporadic and are more likely to occur in young males. The typical clinical manifestations of the Vogt triad are epilepsy, intellectual disability, and facial sebaceous adenoma. Almost all organs in the body can be affected[1-3] (the skin, nervous system, heart, lungs, kidneys, bones, etc.). The main treatment method for TSC is the targeted drug rapamycin. The present patient was a male adolescent with clinical manifestations of epilepsy. The imaging findings included subependymal nodules, bilateral renal angiomyolipomas, and multiple ground glass opacity in both lungs on chest CT. Genetic testing revealed TSC2 gene mutations, consistent with previous literature reports[3].

PLE of the lower limbs is caused by congenital structural and/or functional deficiencies in the lymphatic system, leading to impaired lymphatic return and the accumulation of protein-rich fluid in the interstitial tissue in the skin and subcutaneous soft tissue of the lower limbs. Prolonged and progressive stimulation of adipose tissue ultimately leads to abnormal proliferation of fibrous connective tissue and irreversible fibrosis of adipose tissue. The most common clinical manifestation is obvious swelling of the skin of the lower limbs, with early onset of collapsible oedema. The skin gradually hardens over time, and there is late onset of abnormal thickening and segmental hypertrophy of the affected limb. In severe cases, this condition can lead to "elephantiasis" of the affected limb, bilateral limb asymmetry, and even limb deformities. The pathogenesis may be related to the following gene mutations[4-6]: Vascular endothelial growth factor receptor-3 (VEGFR-3), SRY-related high mobility group Box 18, and forkhead Box C2. The overall incidence rate of PLE is 1-2/100000, and PLE usually occurs in childhood, and there are more women affected than men[4]. The patient was diagnosed with primary lower limb LE through clinical and imaging examinations. The clinical manifestation was swelling of the right lower limb without obvious cause. A typical honeycomb-like pattern (honeycomb sign) was observed in the subcutaneous soft tissue of the right lower limb via MRI, and ⁹⁹Tc^m-DX-lymphoscintigraphy revealed the absence of lymphatic vessels and lymph nodes in the right lower limb accompanied by right lower limb skin lymphatic reflux, which is consistent with the imaging findings of LE reported by Liu et al[7] and Wen et al[8].

According to the literature, TSC with PLE (TSC-PLE) has only been observed in case reports. A summary of all relevant literature retrieved from PubMed from 1986 to 2023 is presented in Table 1. There were a total of 14 articles and 16 cases. Including this case report, there were a total of 17 patients, including 11 females (64.7%) and 6 males (35.3%). There were more women with TSC-PLE than men, with an age range of 0-28 years and an average age of 6.3 years. LE is more common in adolescents than in adults, and LE often occurs in the lower limbs; there was a total of 15 cases (88.2%), and all 15 cases of oedema occurred in one limb (two cases are unknown). There were 3 patients with TSC1 gene mutations, 7 patients with TSC2 gene mutations, and 7 patients with unclear gene mutations. Geffrey et al[9] reported that the incidence rate of PLE in TSC patients was 0.70% (2/286). However, the pathological and physiological mechanisms of TSC-PLE are not yet clear. Among the more than 20 genes involved in lymphatic system development, some are closely related to the mTOR pathway. Therefore, several researchers speculate that there may be five possible reasons for the occurrence of TSC-PLE: (1) The phosphoinositol 3-kinase signalling pathway plays an important role in the formation and remodelling of the lymphatic system. Due to TSC gene mutations, mTOR is activated, thereby inhibiting lymphatic vessel growth. Eventually, the affected limb's lymphatic system develops poorly[10]; (2) VEGFR-3 and VEGF-C are important regulatory factors that promote lymphatic vessel proliferation and cell migration. Studies have shown that VEGF-C can activate downstream mTOR/S6 kinase signalling pathways and that activated mTOR acts through p70S6 kinase[11]; (3) mTOR directly participates in the generation of lymphatic vessels: Studies have shown that the expression of mTOR in lymphatic endothelial cells is significantly increased and that mTOR is abnormally activated in lymphatic malformations[11]; (4) The reason why the incidence rate of female patients with TSC-PLE increases significantly may be related to oestrogen[9]; and (5) Smooth cell hypertrophy: Abnormal smooth cell hypertrophy within subcutaneous tissue compresses superficial lymphatic vessels, leading to impaired lymphatic reflux and ultimately resulting in LE[12].

Table 1 Summary of cases of tuberous sclerosis complex with primary lymphedema from 1986 to 2023.

No	Ref.	Year	Number	Gender	Age (yr)	Edemasite	Gene	Treatment
1	Cottafava et al[16]	1986	1	Female	7	Left lower limb	Unknown	Anti convulsive drugs + anti ACTH drugs
2	Hirsch et al[17]	1999	1	Female	28	Left lower limb	Unknown	Subcutaneous lymphangiectomy + diuretic + elastic socks
3	Voudris et al[18]	2003	1	Female	5	Left lower limb	Unknown	Unknown
4	Lucas and Andrade[19]	2011	1	Female	1	Right lower limb	TSC1	Unknown
5	Sukulal and Namboodiri[12]	2012	1	Female	0	Left lower limb	Unknown	Unknown
6	Navarre and Poitras[13]	2014	1	Male	5	Left lower limb	TSC2	Fasectomy + toe amputation + antibiotics + enoxaparin + warfarin
7	Prato et al[20]	2014	1	Female	4	Left upper limb	TSC2	Carbamazepine + topiramate + everolimus + amoxicillin-clavulanate potassium
8	Geffrey et al[9]	2014	2	Female/Female	8/15	Left lower limb/Left lower limb	TSC2/TSC2	Rapamycin + lymphedema therapy
9	Hoshiai et al[21]	2015	2	Female/Female	2/0	Right lower limb/Right upper limb	Unknown	Unknown
10	Saffari et al[22]	2019	1	Male	6	lower limb but unknown left and right	TSC2	Everolimus
11	Wiemer-Kruel et al[14]	2020	1	Male	7	Left lower limb	TSC2	Levetiracetam + repair of aortic aneurysm + everolimus
12	Kaneshi et al[15]	2020	1	Male	0	lower limb but unknown left and right	Unknown	Ileostomy decompression + antibiotics + lymphedema therapy
13	Lin et al[11]	2020	1	Male	3	Left lower limb	TSC1	Albumin + diuretics
14	Klinner et al[23]	2020	1	Female	0	Right lower limb	TSC1	Aminohexenoic acid + lymphatic drainage + bandage compression
15	This case	2023	1	Male	16	Right lower limb	TSC2	Sirolimus + oxcarbazepine + liposuction

TSC: Tuberous sclerosis complex.

The main treatment for TSC-PLE patients is rapamycin, which can alleviate both TSC-related symptoms and lymphatic vessel abnormality-related symptoms (e.g., LE)[9]. Liposuction and volume reduction surgery can also be performed to reduce lower limb oedema and improve the appearance of the affected limb. In this case, antiepileptic drugs were used to suppress seizures. In addition, when TSC-PLE is combined with other critical signs, such as osteofascial compartment syndrome caused by severe LE, aortic aneurysm caused by severe vascular malformations, erysipelas and systemic infections caused by LE, and pulmonary embolism caused by deep vein thrombosis, timely symptomatic treatment should be administered[13-15].

CONCLUSION

TSC-PLE is a rare, congenital and systemic disease closely related to a variety of gene mutations and is most common among young women, with an overall incidence rate of approximately 0.7%. The clinical manifestations of TSC-PLE are diverse and include epilepsy, memory loss, intellectual disability, lower limb swelling, etc. Multiple imaging methods can detect systemic organ and tissue lesions, which are important for clinical diagnosis and treatment. Rapamycin-targeted therapy is the main treatment method for this disease and can simultaneously treat the symptoms of both TSC and PLE. Liposuction can effectively improve limb swelling in patients However, the specific pathophysiological mechanism of TSC-PLE is still unclear and requires further research.