CLOVES Syndrome: An Unusual Cause of Vascular Malformations and Soft Tissue Overgrowth

Abstract

CLOVES syndrome is a rare congenital disorder characterized by Congenital Lipomatous Overgrowth of the trunk and/or thorax, Vascular malformations, skin abnormalities (such as linear Epidermal nevi), and Skeletal anomalies, with scoliosis and tethered cord being common features. This report presents the case of a 17-year-old boy with clinical and imaging features consistent with CLOVES syndrome, confirmed by genetic analysis demonstrating a somatic PIK3CA mutation.

 

Scroll to top

Keywords

CLOVES - soft tissue overgrowth - vascular malformations

Case Presentation

A 17-year-old boy presented with complaints of intermittent hematuria, right thigh swelling, and soft tissue swelling in the left lower chest wall. He reported no previous history of trauma and his vitals were within normal limits. His past history included multiple soft tissue swellings on the back since birth, previously excised and histopathologically diagnosed as lipoma. Physical examination revealed soft tissue hypertrophy in the left posterolateral chest wall in infrascapular location with intact overlying skin ([Fig. 1A]). Additional findings included sandal gaps in both feet, bilateral wide feet, two to three residual epidermal nevi over the abdomen on the right side, and asymmetric hypertrophy of the right lower limb ([Fig. 1B, C]). Detailed examinations of other systems, including the cardiovascular system, were within normal limits. The laboratory tests (hemoglobin: 12.4 g/dL; total leucocyte count: 5,410/microliter; serum creatinine: 0.4 mg/dL) were normal. Urine microscopic analysis revealed the presence of red blood cells. For better characterization of the soft tissue mass, a contrast-enhanced MRI (magnetic resonance imaging) of the thoracoabdominal region was performed

Fig. 1 Clinical photograph demonstrating soft tissue hypertrophy in the left posterolateral chest wall in infrascapular location (yellow arrow in A), bilateral wide feet with sandal gap (black arrow in B), and epidermal nevi (white asterisk in C).

MRI revealed a soft tissue mass in the infrascapular extra-pleural aspect of the left hemithorax along the posterolateral chest wall extending into the intramuscular and subcutaneous compartment. This lesion appeared heterogeneously hyperintense on T1-weighted images, with areas of signal suppression on fat-saturated sequence indicating fat component ([Fig. 2A, B]). It was also hyperintense on T2-weighted images, with interspersed elongated tubular-appearing vascular channels showing post-contrast enhancement suggestive of a slow-flow venous malformation ([Fig. 2C, D]). No high-flow vascular component was seen. Similar fatty proliferation and vascular anomalies were noted in bilateral perinephric regions, more marked on the right side ([Fig. 2E, F]). Spine showed lumbar scoliosis without evidence of tethered cord or neural tube defects. Lobulated, multiseptated T2 hyperintense lesions representing fat infiltrated within the left epididymis. The vastus lateralis and intermedius muscles on the right side were bulky with T2 hyperintense areas seen in the thigh muscles representing fatty infiltration ([Fig. 3]). Brain MRI was unremarkable. Genetic testing confirmed the presence of a somatic PIK3CA mutation on chromosome 3q26, consistent with diagnosis of PIK3CA-related overgrowth spectrum (PROS). The combination of imaging features—fatty tissue overgrowth, venous malformations in the left back and perinephric region, epidermal nevi, and scoliosis—supported the diagnosis of CLOVES syndrome. The patient underwent ultrasound-guided sclerotherapy for the venous malformations in the left posterolateral back. Over a 1-year follow-up, no progression of the vascular malformations was observed.

Fig. 2 Axial T1 MRI image (A) revealing presence of heterogenous hyperintense soft tissue mass in the extrapleural aspect of left hemithorax along the posterolateral chest wall with extension into the intramuscular and subcutaneous compartments, with areas of signal suppression on fat-saturated T1 image (B) indicating a fat component. It was also hyperintense on axial T2-weighted image (C), with interspersed elongated tubular-appearing vascular channels showing post-contrast enhancement (D), suggestive of a slow-flow venous malformation. Axial (E) and coronal (F) images depicting fatty infiltration and tubular channels in the bilateral perinephric space (shown by white arrow) and presence of scoliosis. MRI, magnetic resonance imaging.

Fig. 3 Coronal image (A) depicting lobulated and multiseptated fatty lesions infiltrating the left epididymis (yellow arrow). Axial image (B) showing bulky right vastus lateralis (VL) and intermedius (VI) muscle with T2 hyperintense fatty areas seen in the thigh muscles (white arrow).

 

Scroll to top

Discussion

CLOVES syndrome is an extremely rare anomaly with estimated incidence of less than 1 in 1,000,000.[1] The pathogenesis of this syndrome has been attributed to somatic mutation in PIK3CA gene mapped to chromosome 3q26.32.[2] It is characterized by Congenital Lipomatous Overgrowth of the trunk and/or thorax, Vascular malformations, skin abnormalities (such as linear Epidermal nevi), and Skeletal anomalies, with scoliosis and tethered cord being common features.[3] Lipomatous hypertrophy can occur in the trunk or extremities, causing asymmetric hypertrophy. The overgrowth can also affect both feet and is “ballooning” in nature.[4] Vascular malformations include venous, capillary, lymphatic, and rarely high-flow malformations. Port wine stains can also be observed in areas of fatty proliferation. Musculoskeletal manifestations include sandal gap toe, ulnar deviation macrodactyly, limb length discrepancy, splayed feet, and syndactyly. Central nervous system manifestations though variable may include gray and white matter abnormalities, polymicrogyria, ventriculomegaly, hemimegalencephaly, corpus callosal dysgenesis, and neural tube defects.[3] Visceral involvement has been reported in the form of renal hypoplasia/agenesis, splenic lesions, and pelvic and retroperitoneal fatty and lymphatic malformations.[5] There is an increased incidence of Wilms tumor in CLOVES syndrome. To the best of our knowledge, there are no published cases in the medical literature describing hematuria as an isolated manifestation of CLOVES syndrome. However, kidney involvement like Wilms tumor or vascular malformation can potentially lead to hematuria as a secondary consequence. In the present case, perirenal vascular malformation could be implicated as the cause of hematuria.

Other PIK3CA-related syndromes include fibro-adipose vascular anomaly, Klippel–Trenaunay syndrome, hemihyperplasia-multiple lipomatosis syndrome, macrodactyly, and megalencephaly-capillary malformation syndrome.[6] PROS encompasses a group of rare syndromes with vascular malformations and soft tissue overgrowth with notable differences in clinical and imaging features. Various common differentials of overgrowth syndromes have been tabulated and are shown in [Table 1].

Table 1 Common differentials of overgrowth syndromes

Features	CLOVES syndrome	Proteus syndrome	Klippel–Trenaunay syndrome
Mutations	PIK3CA gene	AKT-1 gene	PIK3CA gene
Presentation	Overgrowth features at birth: asymmetric and less progressive	Overgrowth features at 6–18 months: increase in severity with age	Port wine stain; limb hypertrophy may be seen at birth, which is progressive
Cutaneous	Epidermal nevi, phlebectasia	Cerebriform overgrowth over palms and soles	Port wine stain
Acral anomalies	Macrodactyly, polydactyly, syndactyly, sandal gap	Macrodactyly	Macrodactyly, polydactyly, syndactyly
Skeletal anomalies	Scoliosis, pectus excavatum, asymmetrical lower limb	Scoliosis, asymmetrical lower limb, soft and bone tissue hypertrophy	Asymmetrical lower limb, soft and bone tissue hypertrophy
Fat malformations	Congenital fat hamartoma affecting trunk, face, limbs and scrotum, retroperitoneum, mediastinum, and thoracic cavity	Acquired fat hypertrophy	Acquired subcutaneous fat overgrowth
Vascular malformations	Low-flow and high-flow vascular anomalies, capillary, venous, and lymphatic malformations	Capillary, venous, and lymphatic malformations	Capillary, venous, and lymphatic malformations with no high-flow component
Neural anomalies	Hemimegalencephaly, corpus callosal dysgenesis	Hemimegalencephaly, developmental delay	Hemimegalencephaly, developmental delay
Complications	Scoliosis, hemoptysis, cardiac failure, pulmonary

Contrast-enhanced MRI and MR angiography are key tools to assess the exact location and extent of vascular malformations and to guide treatment planning. Treatment options for conditions in the PROS spectrum vary and include observation, interventional therapy, conservative management, and surgery.[6] Interventional radiology offers minimally invasive options in the management of vascular anomalies within CLOVES syndrome, ranging from sclerotherapy of symptomatic venous malformations to comprehensive treatment (embolization) of high-flow arteriovenous malformations and spinal/paraspinal arteriovenous fistulas. Recent research has shown that inhibitors of phosphatidylinositol-3-kinase and mTOR (mammalian target of rapamycin) have demonstrated potential roles in treating vascular and lymphatic malformations in the PROS spectrum. The present case illustrates the clinical and imaging findings associated with CLOVES syndrome. A thorough understanding of the radiologic features of various complex overgrowth syndromes and a systematic approach are essential for early and accurate diagnosis and timely management.

 

Scroll to top

 

Scroll to top

Conflict of Interest

None declared.

• References

• 1 Rana A, Sethy A, Krishnan V, Aggarwal A. Ultrasound diagnosis of syndromic cases with vascular malformations and soft tissue overgrowth: a rare case of CLOVES syndrome. Ultrasound 2022; 30 (04) 339-345
• 2 Kurek KC, Luks VL, Ayturk UM. et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet 2012; 90 (06) 1108-1115
• 3 Mahajan VK, Gupta M, Chauhan P, Mehta KS. Cloves syndrome: a rare disorder of overgrowth with unusual features - an uncommon phenotype?. Indian Dermatol Online J 2019; 10 (04) 447-452
• 4 Gucev ZS, Tasic V, Jancevska A. et al. Congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) syndrome: CNS malformations and seizures may be a component of this disorder. Am J Med Genet A 2008; 146A (20) 2688-2690
• 5 Alomari AI. Comments on the diagnosis and management of CLOVES syndrome. Pediatr Dermatol 2011; 28 (02) 215-216
• 6 Ufuk F. Case 289: PIK3CA-related Overgrowth Spectrum (PROS): CLOVES syndrome and coexisting fibroadipose vascular anomaly. Radiology 2021; 299 (02) 486-490

Publication History

Article published online:
07 October 2025