CLOVES Syndrome: A Rare Disorder of Growth

INTRODUCTION

Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevus and Skeletal abnormalities (CLOVES) syndrome, a relatively new overgrowth syndrome, is defined by the acronym CLOVES, which represents congenital lipomatous overgrowth, vascular anomalies, epidermal nevi and skeletal abnormalities.^[1] The pathogenesis is associated with somatic (postzygotic) mutations in the PIK3CA gene located on chromosome 3q26.32.^[2] CLOVES syndrome is exceptionally rare. The prevalence is fewer than one case per million individuals.^[3]

CASE REPORT

A 10-month-old boy, born to otherwise non-consanguineous and healthy parents, presented to the outpatient department of dermatology with swelling over left side of face and pigmented skin lesions over neck since birth. The child had normal developmental milestones and was immunised for his age. His family and medical history showed no notable abnormalities. On examination, we noticed an asymmetrical swelling over left side of face extending from parietal bone up to the angle of mandible [Figure 1a] and verrucous epidermal nevus extending from left pre- and post-auricular area, neck and upper left shoulder [Figure 1b]. Sandal gap deformity was present bilaterally between 1^st and 2^nd toe, along with bilateral hypertrophy of the second toe of the feet [Figure 1c]. No bony, visceral, ocular and dental anomalies were detected. X-rays of both feet revealed widening of web spaces between 1^st and 2^nd toe and enlarged metapahalenges [Figure 2]. X-ray of whole abdomen revealed no abnormality [Figure 3]. Contrast-enhanced computed tomography head showed large non-capsulated subcutaneous fat extending from the left parietal bone to angle of mandible with fatty infiltration of the left parotid gland, masseter, temporalis, buccinator, lateral and medial pterygoid muscles, intrinsic and extrinsic muscles of left side of tongue muscle, hypertrophy of left mandible and left zygomatic arch [Figure 4]. Ultrasonography Doppler of the anterior abdominal wall mass showed no vascular malformation. Genetic workup was not done due to financial constraints and non-availability at our hospital.

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Figure 1:

(a) Asymmetrical swelling over left side of face extending from parietal bone up to the angle of mandible, (b) verrucous epidermal nevus extending from left pre and post auricular area, neck and upper left shoulder and (c) sandal gap deformity between 1^st and 2^nd toe present bilaterally along with bilateral hypertrophy of the second toe of the feet.

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Figure 2:

X-rays of both feet (anteroposterior and lateral view) showing widening of web spaces between 1^st and 2^nd toe and enlarged metapahalenges.

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Figure 3:

X-ray of whole abdomen showing no abnormality.

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Figure 4:

Contrast-enhanced computed tomography head showing large non-capsulated subcutaneous fat extending from left parietal bone to angle of mandible with fatty infiltration of left parotid gland, masseter, temporalis, buccinator, lateral and medial pterygoid muscles, intrinsic and extrinsic muscles of the left side of tongue muscle, hypertrophied condylar process, hypertrophy of left mandible and left zygomatic arch.

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DISCUSSION

CLOVES syndrome (OMIM number 612918) is a rare, sporadic and complex mosaic overgrowth syndrome. It is now classified under the umbrella of PIK3CA-Related Overgrowth Spectrum (PROS) characterised by postzygotic activating somatic mutations in the PIK3CA gene, which is located on chromosome 3q26.32.^[4] It presents as congenital overgrowth of adipose tissue across various body regions and tissue spaces and unilateral or bilateral lipomatous masses, particularly prominent on the thoracic and abdominal walls.^[5] CLOVES syndrome is characterised by capillary malformation (including low-flow and geographic patterns), venous anomalies (such as superficial phlebectasia), lymphatic abnormalities (including macrocystic, microcystic or mixed presentations) and arteriovenous malformations.^[5] Epidermal nevi is either congenital or develop in childhood and is usually found on the neck, abdomen, flank or limbs. Skeletal malformations in CLOVES syndrome often present as scoliosis and asymmetric enlargement of skeletal structures in the extremities. Scoliosis may be congenital or develop during childhood, possibly due to lower limb asymmetry.^[6] Other musculoskeletal manifestations include leg length discrepancy, genu recurvatum, polydactyly, syndactyly, splayed feet and sandal gap (widened first toe web).^[7]

The diagnosis of CLOVES syndrome remains clinical, but it must be differentiated from other PROS disorders, particularly from Proteus syndrome and Klippel-Trenaunay syndrome, as mentioned in Table 1.^[8,9]

We made the diagnosis of CLOVES syndrome in our patient based on diagnostic criteria by Keppler-Noreuil et al., as mentioned in Table 2.^[8,9]

Managing CLOVES syndrome requires a comprehensive, multidisciplinary approach personalised to each patient’s specific needs. Treatment strategies include surgical debulking for lipomatous overgrowths, sclerotherapy and embolisation for vascular malformations, pulse-dye lasers for capillary malformations and epiphysiodesis for limb length discrepancies.^[10] The Food and Drug Administration granted accelerated approval to Alpelisib (Vijoice, Novartis Pharmaceuticals) on 5 April 2022, for treating severe manifestations of PROS in adult and paediatric patients aged 2 years and older who need systemic therapy.^[11]

CONCLUSION

CLOVES syndrome is exceptionally rare, and research in this area is predominantly limited to a scant body of published literature. Herein, we report a case of a 10-month-old baby with CLOVES syndrome. We are presenting this case to contribute to medical literature by providing a comprehensive account on CLOVES syndrome.