Renal vein thrombosis as a reversible vascular renal complication of CLOVES syndrome: a case report

Abstract

PIK3CA-related overgrowth spectrum (PROS) comprises mosaic gain-of-function variants in PIK3CA that lead to segmental overgrowth and complex vascular malformations. Renal involvement has been inconsistently described and mainly includes glomerulomegaly and focal segmental glomerulosclerosis. We report a 39-year-old woman with a phenotypic diagnosis of CLOVES syndrome molecularly supported by a somatic mosaic PIK3CA variant, NM_006218.4:c.1634 A > C, p.Glu545Ala, detected in affected hypertrophic tissue. She presented with acute kidney injury and subnephrotic-range proteinuria secondary to left renal vein thrombosis. Imaging revealed intrarenal venous congestion in the setting of extensive abdominal venous malformations. Anticoagulation resulted in complete radiologic and functional recovery. Renal vein thrombosis should be considered as a potentially reversible vascular cause of acute kidney injury and proteinuria in patients with CLOVES syndrome/PROS, particularly in the presence of extensive venous malformations.

Introduction

PIK3CA-related overgrowth spectrum (PROS) comprises a group of mosaic disorders caused by postzygotic activating variants in PIK3CA, encoding the catalytic subunit p110α of phosphoinositide 3-kinase alpha (PI3Kα). Constitutive activation of the PI3K–AKT–mTOR pathway drives dysregulated cellular proliferation, survival, angiogenesis, and metabolic signaling, resulting in asymmetric tissue overgrowth and complex vascular malformations. The phenotypic variability observed in PROS reflects the timing and tissue distribution of the somatic variant, with CLOVES syndrome representing one of the most severe clinical presentations [1].

Beyond structural overgrowth, PI3Kα signaling has been implicated in renal pathology. Experimental and translational data suggest that dysregulated PI3K–AKT–mTOR signaling may contribute to glomerular hypertrophy, podocyte enlargement, mesangial expansion, and endothelial dysfunction. Mosaic PIK3CA variants have been identified in glomerular epithelial cells, raising the possibility that aberrant PI3K signaling may contribute to otherwise unexplained kidney dysfunction. The pathway has also been studied in inflammatory and proliferative nephropathies, including lupus nephritis and diabetic kidney disease [2, 3].

Vascular malformations are a defining feature of PROS, and abnormal endothelial PI3K signaling promotes angiogenic dysregulation and altered hemostatic balance [4, 5]. However, the spectrum of renal vascular complications in PROS remains incompletely characterized.

Case report

A 39-year-old woman with a phenotypic diagnosis of CLOVES syndrome molecularly supported by a somatic mosaic PIK3CA variant presented with acute worsening of kidney function, new-onset hypoalbuminemia, and subnephrotic-range proteinuria.

The patient had a long-standing phenotypic diagnosis of CLOVES syndrome within the PIK3CA-related overgrowth spectrum. Her phenotype was characterized by congenital-onset and progressive segmental overgrowth, predominantly involving the lower extremities, with marked asymmetric soft-tissue hypertrophy, macrodactyly/splayed feet, increased plantar soft tissue, and previous reduction procedures for overgrown acral soft tissues. Additional features included cutaneous hyperpigmented lesions following Blaschko lines, areas resembling epidermal nevus, lipomatous overgrowth, skeletal abnormalities including scoliosis, and extensive vascular/lymphatic malformations. These clinical findings supported the diagnosis of CLOVES syndrome, which was subsequently molecularly supported by detection of a somatic mosaic PIK3CA variant in affected hypertrophic tissue.

For molecular confirmation, a biopsy specimen was obtained from hypertrophic tissue of the left lower extremity. Next-generation sequencing–based full-gene analysis of PIK3CA was performed on this tissue sample, including the coding regions and exon–intron boundaries. The analysis identified a somatic mosaic PIK3CA variant, NM_006218.4:c.1634 A > C, p.Glu545Ala, with a variant allele fraction of 11%. The variant was reported as likely pathogenic. These findings supported the clinical diagnosis of PIK3CA-related overgrowth spectrum, with the patient’s phenotype being most consistent with CLOVES syndrome.

Previous renal and laboratory evaluations did not suggest pre-existing intrinsic kidney disease. Her baseline serum creatinine was 0.6 mg/dL, serum albumin was 3.9 g/dL, and total serum protein was 7.4 g/dL. Previous urinalysis showed neither proteinuria nor hematuria. The lipid profile was not suggestive of nephrotic physiology, with an LDL cholesterol level of 120 mg/dL, and coagulation parameters were within the normal range. At the time of presentation, serum creatinine increased to 1.07 mg/dL, serum albumin decreased to 2.8 g/dL, and 24-hour urinary protein excretion was 1.7 g/day. Urinalysis revealed microscopic hematuria with approximately 20 erythrocytes/high-power field, without gross hematuria. The patient did not report flank pain, and blood pressure was elevated compared with previous measurements.

Contrast-enhanced computed tomography demonstrated acute thrombosis of the left renal vein, accompanied by intrarenal venous congestion (Fig. 1). Extensive abdominal venous malformations consistent with the patient’s PROS phenotype were observed.

Fig. 1.

Clinical and radiologic features of CLOVES syndrome with renal vein thrombosis. (A) Asymmetric lower-extremity overgrowth with marked soft tissue hypertrophy and cutaneous hyperpigmented patches. (B1-B2) (coronal and axial venous-phase images) Contrast-enhanced CT demonstrating an intraluminal filling defect within the left renal vein

The patient was evaluated by interventional radiology and cardiovascular surgery. Therapeutic anticoagulation with twice-daily enoxaparin was initiated. One week later, Doppler ultrasonography confirmed complete resolution of the thrombus and disappearance of intrarenal venous congestion without residual filling defects. Repeat contrast-enhanced CT was not performed because follow-up Doppler ultrasonography demonstrated complete thrombus resolution and additional contrast-enhanced CT was not considered clinically necessary. Serum creatinine returned to baseline, proteinuria regressed significantly, and blood pressure stabilized.

Discussion

This case highlights renal vein thrombosis with ipsilateral renal venous congestion as a potentially reversible vascular mechanism of kidney dysfunction in CLOVES syndrome. Although renal enlargement and glomerular lesions have previously been described in PIK3CA-related overgrowth spectrum, the acute renal manifestations in the present patient are most consistently explained by venous outflow obstruction rather than by a primary intrinsic glomerular proliferative process.

The patient had extensive venous and lymphatic malformations, a well-recognized component of CLOVES syndrome. Such vascular abnormalities may predispose to local flow disturbance and venous stasis, thereby increasing the risk of thrombosis. In this setting, acute left renal vein thrombosis provides a plausible explanation for the concurrent deterioration in kidney function, new-onset subnephrotic proteinuria, microscopic hematuria, and blood pressure elevation. The absence of prior proteinuria or hematuria, preserved baseline kidney function, normal baseline serum albumin, absence of nephrotic-range proteinuria or marked dyslipidemia, normal coagulation parameters, and rapid improvement after anticoagulation further support a vascular/hemodynamic mechanism.

Although the absence of renal biopsy precludes definitive exclusion of an underlying glomerular lesion, the patient’s previously normal urinalysis, preserved baseline renal function and serum albumin, lack of nephrotic-range proteinuria or marked dyslipidemia, normal coagulation parameters, and rapid improvement after anticoagulation favor an acute hemodynamic mechanism related to renal venous thrombosis and congestion rather than pre-existing nephrotic physiology as the primary driver of thrombosis.

Although aberrant PI3Kα signaling is central to the pathogenesis of PROS and may contribute to abnormal vascular development, this case does not provide direct histopathologic evidence of renal PI3K pathway activation, endothelial proliferation, or glomerular proliferation. Therefore, the mechanistic interpretation should remain cautious. The clinically relevant message is that renal vein thrombosis should be actively considered as a treatable cause of acute kidney injury and proteinuria in patients with CLOVES syndrome, particularly when extensive venous malformations are present.

Author contributions

Z.U. was responsible for the conception and design of the study, data collection, analysis, interpretation, and drafting of the manuscript.

Funding

No funding was received for this study.

Data availability

The data supporting the findings of this study are not publicly available due to patient privacy and ethical restrictions. However, the data are available from the corresponding author (Z.U.) upon reasonable request.

Declarations

Conflict of interest

The author declares that there is no conflict of interest.

Ethical approval

This article does not contain any experimental studies performed by the author. According to institutional policy, ethical committee approval was not required for this single case report.

Informed consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images.