Ultrasound diagnosis of syndromic cases with vascular malformations and soft tissue overgrowth: A rare case of CLOVES syndrome

Introduction

Ultrasound is the initial investigation of choice for the evaluation of soft tissue swellings in paediatric population. ¹ Vascular anomalies are a common cause of paediatric soft tissue swellings and are easily assessed on ultrasound. Colour Doppler examination provides dynamic assessment of lesion vascularity, arterial and venous flow and velocity measurement. ² Several complex syndromes are associated with such vascular anomalies that can be suspected or even diagnosed on ultrasound alone. Accurate diagnosis of such syndromes is often considerably delayed, missing the critical period of rapid growth. Recent advances in the management of such syndromes can considerably limit the resulting deformities if initiated early. One such syndrome is CLOVES, an exceedingly rare limb overgrowth syndrome which stands for congenital lipomatous overgrowth (CLO), vascular malformations (V), epidermal nevi (E) and spinal/skeletal anomalies/scoliosis (S). ³ Here, we have explored a case of CLOVES syndrome which was diagnosed in a patient referred for the assessment of soft tissue swellings, solely based on detailed clinical and ultrasound findings. We have also discussed how related syndromes can be differentiated and diagnosed in patients referred for ultrasound of soft tissue swellings.

Case report

A 6-year-old girl presented with gradually progressive swelling of the left ring finger and bluish discolouration over the right ankle since birth. On clinical examination, multiple swellings were present over her back, anterior abdominal wall and left distal leg. Bluish clustered papules were seen over the right ankle, consistent with epidermal nevi (Figure 1). The child’s younger sibling also had similar signs and symptoms. No other family members were affected. The child was referred to the radiology department for ultrasound evaluation of the soft tissue swellings.

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Figure 1.

Clinical photographs of the child showing enlargement of left ring finger (a and b), swelling over left distal leg with bluish discolouration of overlying skin (black arrow in c), swelling over paraspinal region (white arrow in d) and right flank (black arrow in d), swelling over left subcostal region (white asterisk in e) and epidermal nevi over right ankle (f).

Grey scale ultrasound with colour Doppler was performed using Philips iU22 scanner with 5–12 MHz linear probe. Ultrasound of left ring finger swelling showed heterogeneous hypoechoeic soft tissue overgrowth. Multiple vascular channels were seen within the soft tissue overgrowth. On spectral Doppler, arterial flow was seen within the vascular channels with arterialized venous waveform in the draining veins. Broadening of proximal and middle phalanges with overlying soft tissue enlargement was seen on ultrasound which was confirmed on radiograph, with no bony lesion seen on the radiograph. There were no calcific foci in the enlarged soft tissue. Findings were suggestive of arteriovenous malformation (AVM) of ring finger with macrodactyly (Figure 2). Ultrasound evaluation of the paraspinal swelling also demonstrated a cluster of anechoic tubular channels with high velocity low-resistance arterial waveform with spectral broadening and arterialized venous waveform, consistent with paraspinal AVM. Evaluation of left distal leg swelling showed tubular anechoic channels with only venous flow on spectral Doppler, suggestive of venous malformation (Figure 3). The swelling over left subcostal region showed increased fat deposition in subcutaneous plane compared to the right subcostal region, consistent with lipomatous overgrowth. Similar lipomatous overgrowth was also seen in subcutaneous plane over right flank (Figure 4). Radiograph of the spine was normal.

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Figure 2.

Ultrasound and colour Doppler images of left ring finger swelling showing heterogeneous hypoechoeic soft tissue overgrowth (a) with multiple vascular channels within the soft tissue overgrowth (b). Spectral Doppler shows arterial waveform within the vascular channels (c). PA radiograph of left hand (d) showing macrodactyly of the ring finger. There is broadening of proximal and middle phalanges with overlying soft tissue enlargement. There is no bony lesion or calcific focus in enlarged soft tissue. Findings are suggestive of arteriovenous malformation of ring finger with macrodactyly.

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Figure 3.

Ultrasound and colour Doppler images of paraspinal swelling showing cluster of anechoic tubular channels (a) with complete vascular fill-in (b). Spectral Doppler images show high-velocity low-resistance arterial waveform with spectral broadening (c) and arterialised venous waveform (d), suggestive of paraspinal arteriovenous malformation (Figure 3). Ultrasound and colour Doppler images of left distal leg swelling showing tubular anechoic channels (e) with only venous flow on spectral Doppler (f), consistent with venous malformation over left distal leg (Figure 3).

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Figure 4.

Ultrasound images of swelling over left subcostal region and right flank show increased fat deposition in subcutaneous plane on left side compared to right, consistent with lipomatous overgrowth (white arrow in a). Similar lipomatous overgrowth is seen in subcutaneous plane over right flank (white arrow in b).

Considering the congenital nature of the lesions, family history, clinical phenotype, ultrasound, and colour Doppler findings, a provisional diagnosis of CLOVES syndrome was made. Genetic testing revealed PIK3CA gene mutation on chromosome 3q26, confirming the diagnosis of CLOVES syndrome. The child was re-evaluated with abdominal ultrasound for evaluation of both kidneys in view of increased risk for Wilms tumour, which turned out to be normal. Embolization therapy for AVM and sclerotherapy for venous malformation were planned for management.

Discussion

CLOVES syndrome was first described by JC Sapp et al. ⁴ in 2007 in seven patients who were initially diagnosed with Proteus syndrome. It is extremely rare with estimated incidence rate less than 1:1,000,000 and has an equal incidence in males and females. ⁵ It is caused by spontaneous somatic mutation in PIK3CA gene on chromosome 3q26 during embryogenesis. PI3K and mTOR signalling pathway is responsible for cellular growth and angiogenesis. Mutation in this pathway causes hamartomatous tumoural growth and abnormal proliferation of blood vessels, lymphatics, bone and muscle. There are no identified risk factors. 2018 ISSVA diagnostic criteria for CLOVES syndrome include venous malformations, lymphatic malformations, capillary malformations, and limb overgrowth with or without associated AVM. ¹ Thoracic and/or truncal lipomatous hyperplasia, paraspinal or spinal AVM and epidermal nevi are the key features for diagnosing CLOVES syndrome.^6,7 Most common vascular anomaly in CLOVES is lymphatic malformation, and it can be microcytic or macrocystic. Slow flow malformations are seen in majority of cases of CLOVES but high flow AVMs are rare. ⁶ An AVM consists of a cluster of vessels demonstrating high-flow with an enlarged feeding artery and draining vein and no intervening capillary bed. ¹ High-flow spinal and paraspinal malformations may lead to spinal cord myelopathy. ⁸ Lipomatous hypertrophy can also affect the trunk and extremities resulting in asymmetric overgrowth or hemihypertrophy. ⁹ Capillary malformations in the form of port wine stains may be seen concurrently in areas of lipomatous overgrowth. ⁷ Musculoskeletal anomalies most frequently affect the extremities predominantly hands and feet. These include macrodactyly, sandal gap toe, and ulnar deviation of hands. Spinal anomalies like scoliosis and spina bifida and pectus deformity may also be seen. ⁷ In our case, CLOVES syndrome was suspected on the basis of clinical features of macrodactyly and epidermal nevi with venous malformation, AVMs, and lipomatous hypertrophy on ultrasound. There is increased incidence of Wilms tumour in CLOVES syndrome compared to general population (3.3% in CLOVES syndrome patients versus 0.01% in general population). Once the diagnosis of CLOVES syndrome is made, screening with abdominal ultrasound should be performed every 3 months till 7 years. ¹⁰ Intervention radiologists, neurosurgeons, orthopaedic and general surgeons, all play a role in the management of vascular lesions, skeletal anomalies and tissue overgrowth. Oral sirolimus (mTOR inhibitor) is indicated for microcystic lymphatic malformation. Ultrasound-guided sclerotherapy is useful for treatment of venous and lymphatic malformations in CLOVES syndrome. Combination of embolization and surgery is used for treating spinal and paraspinal high-flow malformation. ¹ Life expectancy and long-term prognosis depend on age at diagnosis (as early diagnosis aids in early initiation of management), anatomical location, and type of vascular malformations and overall health.

Major differential diagnoses of CLOVES syndrome are Klippel–Trenaunay syndrome (KTS), Proteus syndrome, Parks Weber syndrome (PWS) and fibroadipose vascular anomaly (FAVA).^1,11 These also present with vascular malformations with soft tissue overgrowth. Ultrasound plays a pivotal role in their differentiation. While evaluating such a patient, if ultrasound of a soft tissue swelling demonstrates vascular malformation, then flow and velocity assessment should be done. Presence of high flow is suggestive of either CLOVES syndrome or PWS. If malformations are seen in upper and lower extremities, spinal and paraspinal region, it is suggestive of CLOVES syndrome. Predominant lower extremity involvement indicates PWS. Absence of high flow and presence of low flow malformations suggests KTS or Proteus syndrome. In such cases, detailed ultrasound evaluation of the affected extremity should be performed to look for the presence of persistent embryonic vein which is characteristic of KTS. In the presence of embryonic vein, deep venous system should be carefully assessed on ultrasound, as it may be absent or underdeveloped. When evaluating the soft tissue overgrowth on ultrasound, the lipomatous proliferation should be further analysed to identify whether it is diffuse or well demarcated. The presence of a well-demarcated fibrofatty intramuscular lesion on ultrasound is suggestive of FAVA. Diffuse unilateral limb overgrowth with lipomatous proliferation and other soft tissue and bone hypertrophy is seen in KTS and PWS, which can be differentiated on the basis of vascular malformation as already described. Asymmetrical lipomatous proliferation and asymmetric acral overgrowth is seen in CLOVES and Proteus syndrome. Rapidly progressing lipomatous overgrowth is seen postnatally at 6–18 months in Proteus syndrome in contrast to CLOVES syndrome, where it is congenital. Lipomatous hyperplasia in the thoracic region is a key feature of CLOVES syndrome.^1,11 The ultrasound assessment protocol is detailed in Flowchart 1.

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Flowchart 1.

Systematic ultrasound approach for assessment of syndromic cases with vascular malformation and soft tissue overgrowth.

Thus, in any child with vascular malformation or soft tissue overgrowth, it is imperative to perform a thorough physical examination for additional swellings. Assessing every soft tissue swelling carefully on ultrasound and following a systematic ultrasound approach may aid in arriving at an accurate diagnosis of complex syndromes. Early diagnosis on ultrasound helps in timely management and prevention of permanent disabilities in such syndromic cases.

Conclusion

Ultrasound plays an important role in the evaluation of soft tissue swellings in the paediatric population. Furthermore, it is possible to systematically analyse the vascular malformations and lipomatous hypertrophy in such cases in order to accurately diagnose complex syndromes with vascular malformations and soft tissue overgrowth. Ultrasound also plays an important role in tumour screening in syndromic cases, ultrasound-guided sclerotherapy and follow-up of vascular lesions after embolization or sclerotherapy.