CLOVES Syndrome: An Unusual Presentation of a Rare Entity : Indian Journal of Paediatric Dermatology

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Case Report

CLOVES Syndrome: An Unusual Presentation of a Rare Entity

Hegde, Pallavi; Choubey, Vikrant1; Sahoo, Bijaylaxmi

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Indian Journal of Paediatric Dermatology: Oct–Dec 2022 - Volume 23 - Issue 4 - p 306-308
doi: 10.4103/ijpd.ijpd_60_21
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Abstract

Introduction

Vascular malformation with limb overgrowth syndromes is a group of clinically and etiologically heterogeneous and rare disorders, CLOVES syndrome being one of them.[1] Cases of CLOVES syndrome reported in the literature till date are limited in number. This report serves to describe such a rare case with undescended testis, which in itself is an unusual finding.

Clinical Case

An 8-year-old male child presented to our outpatient department with complaints of reddish-blue fluid filled lesions over the right side of the trunk with occasional bleeding subject to minor trauma for the past 1 year. On mucocutaneous examination, multiple hemorrhagic to clear fluid-filled vesicles were present over right side of the trunk with sharp midline cutoff [Figure 1a]. On puncturing these lesions with a sterile needle, extrusion of hemorrhagic fluid was seen. On dermoscopy, half-and-half blisters were noted, suggestive of microcystic lymphatic malformation/mixed malformation [Figure 1b]. Multiple capillary malformations were present on back, chest, both upper limb, palmar aspect of both, thumb, and index finger [Figure 1c]. A subtle hyperpigmented macule with mild overlying hypertrichosis in a blaschkoid distribution was present at the upper back suggestive of an epidermal nevus [Figure 2]. On anthropometric assessment, the child had overgrowth of all four limbs. The length of limbs and mid-upper arm circumference was comparatively more on the left side. Musculoskeletal examination revealed macrodactyly of all 20 digits, syndactyly of second and third toes on both sides [Figures 3a and b], scoliosis and lordosis [Figure S1 in the Supplementary Appendix]. In addition, the testis on the left side was not palpable [Figure S2 in the Supplementary Appendix]. There were no similar complaints in family members. The postnatal period was uneventful and developmental milestones were appropriate as per the age. Based on history and clinical examination, we classified the patient as a case vascular malformation with limb overgrowth syndrome, most likely CLOVES syndrome, and the patient was further investigated.

F1
Figure 1:
(a) Lymphangioma circumscriptum over trunk. (b) Dermoscopy of truncal vesicles showing both clear and hemorrhagic fluid, described typically as half-and-half blisters. (c) Capillary malformations over back and arms
F2
Figure 2:
Epidermal nevus in a blaschkoid pattern on upper back on the left side
F3
Figure 3:
(a) Macrodactyly, most pronounced in middle finger. (b) Macrodactyly of toes along with syndactyly of second and third toes
F4
Figure S1:
Spinal abnormalities noted on clinical examination. In (a), scoliosis is demonstrated, whereas (b) shows lordosis
F5
Figure S2:
Undescended testis. The scrotal sac on the left side was devoid of any palpable testis, suggestive of undescended testis

Histopathology of truncal lesions showed multiple dilated spaces in epidermis filled with both clear fluid and red blood cells, the surrounding rete ridges were elongated and were encircling the lesions, which was suggestive of mixed malformation. Histopathology of epidermal nevus showed mild hyperkeratosis, acanthosis, and papillomatosis [Figure S3]. Bony and soft tissue overgrowth of all limbs and kyphoscoliosis were confirmed radiologically. Ultrasonography, Doppler and magnetic resonance imaging of truncal lesions showed few dilated tortuous anechoic vascular channels in subcutaneous plane with prominent subcutaneous fat suggestive of slow flow malformation. Ultrasonography and Doppler scan of 4 limbs and magnetic resonance imaging of brain, spine, and spinal cord were normal. Based on history, clinical findings, and investigations, the patient fulfilled the diagnostic criteria for phosphatidyl inositol kinase 3 catalytic alpha (PIK3CA) Related Overgrowth Syndrome, typically CLOVES syndrome.[2]

F6
Figure S3:
Histopathology of epidermal nevus. The black arrow shows hyperkeratosis, blue arrow shows acanthosis and sparse inflammatory infiltrate in dermis is shown by orange arrow

Discussion

CLOVES syndrome is a recently described rare entity with a total of less than 200 cases reported worldwide.[1-3] Few clinical features from previously diagnosed patients of Proteus syndrome were originally delineated and the acronym CLOVE was coined, encompassing the following: Congenital Lipomatous Overgrowth, Vascular malformations, and Epidermal Nevi syndrome.[1] Subsequently, based on the addition of skeletal and spinal abnormalities, the acronym was further expanded to CLOVES.[3] The pathogenesis of CLOVES syndrome is attributed to somatic postzygotic activating mutations in PIK3CA leading to excessive activation of Akt-mTOR cell-signaling pathway.[4]

CLOVES syndrome is characterized by progressive, complex, and mixed primarily truncal vascular malformations, which are typically slow flow but high flow malformations have also been described.[135-7] These malformations can extend into adjacent body cavities/internal organs too.[68]

Dysregulated adipose tissue growth presenting as truncal mass is another key feature of CLOVES. This mass might contain vascular content within it.[15] It can infiltrate into adjacent areas similar to malformation.[6] In our patient, the slow flow malformation noted in the subcutaneous plane of the trunk was associated with abnormally prominent adipose tissue around it.

The most commonly described musculoskeletal anomaly is a congenital overgrowth of hands and feet that grow proportionately with the patient.[139] Macrodactyly, typically involving the third digit, syndactyly, and polydactyly are the other reported entities.[157910] Varying degrees of scoliosis, lordosis, and other skeletal deformities are also known in CLOVES syndrome.[13] Most of these features were present in our patient.

Epidermal nevus is the least common of classical findings in CLOVES syndrome. It is to be noted that the lesion in our patient was very subtle and could have been missed if not for an extensive close physical examination.

In addition, our patient also demonstrates an empty scrotal sac on the left side. On clinical examination, a testicle was palpated in the perineum and the same was confirmed on ultrasonography. This was a unique finding in our patient, previously underreported.

Apart from classical mucocutaneous and musculoskeletal description of CLOVES as above, neonatal CLOVES is another more severe variant, generally carrying grave prognosis.[68] Systemic involvement is also well known in CLOVES syndrome [Table S1 in the Supplementary Appendix].[158]

T1
Table S1:
Anthropometric parameters for limb overgrowth assessment

The differential diagnosis includes other entities amongst “vascular malformation with limb overgrowth syndromes.” [Table S2 and Table S3 in the Supplementary Appendix] Although CLOVES syndrome is most often misdiagnosed as Proteus syndrome, a clear demarcation between all these entities is possible with a detailed evaluation. Furthermore, identifying the disorder per se should help understand these disorders in terms of etiopathogenesis, clinical features, prognosis, and treatment.

T2
Table S2:
Systemic involvement described in congenital lipomatous overgrowth, vascular malformations, and epidermal nevi syndrome
T3
Table S3:
Differentiating features between various “vascular malformation with limb overgrowth syndromes”

Conclusion

CLOVES syndrome is a rare disorder that requires a better understanding of its clinical features and etiopathogenesis, so as to differentiate from other overgrowth syndromes with similar presentation. This is important not only for purposes of management but also for academics and research. Our patient had undescended testis which has been reported only once to the best of our knowledge. As more data pertaining to this entity emerge, there is a potential for further expansion of clinical spectrum of the disease. It is also important to stress on extensive examination so that subtler findings such as epidermal nevi do not go unnoticed.

Declaration of consent

The authors certify that they have obtained all appropriate consent forms, duly signed by the parent(s) of the patient. In the form the parent(s) has/have given his/her/their consent for the images and other clinical information of their child to be reported in the journal. The parents understand that the names and initials of their child will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1. Sapp JC, Turner JT, van de Kamp JM, van Dijk FS, Lowry RB, Biesecker LG Newly delineated syndrome of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome) in seven patients Am J Med Genet A 2007 143 A 2944 58
2. 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 10 447 52
3. Alomari AI CLOVE (S) syndrome:Expanding the acronym Am J Med Genet A 2009 149 A 294
4. Kurek KC, Luks VL, Ayturk UM, Alomari AI, Fishman SJ, Spencer SA, et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome Am J Hum Genet 2012 90 1108 15
5. Alomari AI Characterization of a distinct syndrome that associates complex truncal overgrowth, vascular, and acral anomalies:A descriptive study of 18 cases of CLOVES syndrome Clin Dysmorphol 2009 18 1 7
6. Acosta S, Torres V, Paulos M, Cifuentes I CLOVES syndrome:Severe neonatal presentation J Clin Diagn Res 2017 11 TR01 3
7. Alomari AI, Chaudry G, Rodesch G, Burrows PE, Mulliken JB, Smith ER, et al. Complex spinal-paraspinal fast-flow lesions in CLOVES syndrome:Analysis of clinical and imaging findings in 6 patients AJNR Am J Neuroradiol 2011 32 1812 7
8. Anderson S, Brooks SS An extremely rare disorder of somatic mosaicism:CLOVES syndrome Adv Neonatal Care 2016 16 347 59
9. Gucev ZS, Tasic V, Jancevska A, Konstantinova MK, Pop-Jordanova N, Trajkovski Z, 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 146 A 2688 90
10. Harit D, Aggarwal A CLOVE syndrome with nevus unis lateris:Report of a case Pediatr Dermatol 2010 27 311 2
Keywords:

CLOVES; proteus; vascular malformation; limb overgrowth; pediatric dermatology

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