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Review
. 2022 Apr 13:15:621-630.
doi: 10.2147/CCID.S351637. eCollection 2022.

A Review on Cutaneous and Musculoskeletal Manifestations of CLOVES Syndrome

Emel Öztürk Durmaz  1 , Deniz Demircioğlu  1 , Pınar Yalınay Dikmen  2 , Yasemin Alanay  3 , Ahmet Alanay  4 , Cüyan Demirkesen  5 , Fatma Tokat  5 , Ercan Karaarslan  6
Affiliations
Review

A Review on Cutaneous and Musculoskeletal Manifestations of CLOVES Syndrome

Emel Öztürk Durmaz et al. Clin Cosmet Investig Dermatol. .

Abstract

CLOVES syndrome is a novel sporadic mosaic segmental overgrowth syndrome, currently categorized under the canopy of PROS (PIK3CA-related overgrowth spectrum) disorders. All PROS disorders harbor heterozygous postzygotic activating somatic mutations involving the PIK3CA gene. As an upstream regulator of the PI3K/AKT/mTOR signal transduction pathway, activating mutations of PIK3CA gene commence in uncontrolled growth of cutaneous, vascular (capillaries, veins, and lymphatics), adipose, neural, and musculoskeletal tissues. The excessive growth is segmental, patchy, asymmetric, and confined to body parts affected by the mutation. The term 'CLOVES' is an acronym denoting congenital lipomatous overgrowth, vascular malformations, epidermal nevi and spinal (scoliosis) and/ or skeletal anomalies. The syndrome is characterized by an admixture of overgrown tissues, derived mainly from mesoderm and neuroectoderm. Among PROS disorders, CLOVES syndrome represents the extreme end of the spectrum with massive affection of almost the entire body. The syndrome might judiciously be treated with medications hampering with the PI3K/AKT/mTOR signal transduction pathway. This article aims at reviewing the cutaneous and musculoskeletal manifestations of CLOVES syndrome, as the paradigm for PROS disorders. CLOVES syndrome and other PROS disorders are still misdiagnosed, underdiagnosed, underreported, and undertreated by the dermatology community.

Keywords: CLOVES syndrome; PIK3CA-related overgrowth spectrum; cutaneous manifestations; epidermal nevi; lipomas; lymphangiomas; port wine stains.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Predominantly left-sided lipomatous tumefactions and scoliosis in a patient with CLOVES syndrome. Note incision scars from previous operations and paucity of adipose tissue in unaffected body areas.
Figure 2
Figure 2
Sacral midline lipomatous mass associated with a sacrococcygeal dimple, complicated with fibrosis and anterior angulation of coccyx. There was no evidence of an occult spinal dysraphism or cord tethering in radio imaging studies.
Figure 3
Figure 3
(A) Translucent blister filled with a clear fluid, typical of superficial lymphangioma/lymphangiectasia. (B) Dermatoscopy revealing yellowish structureless areas.
Figure 4
Figure 4
(A) Biopsy of a lymphangioma/ lymphangiectasia: Dilated lymphatic channels within the upper dermis (H&E X 20). (B) Endothelial cells displaying immunoreactivity with D2-40 (podoplanin) monoclonal antibody (IHC X 100).
Figure 5
Figure 5
(A) Hemolymphangioma/hemolymphangiectasia caused by intra-lesional bleeding into a lymphangioma/lymphangiectasia. (B) Dermatoscopy revealing vascular lacunes.
Figure 6
Figure 6
Wide triangular left foot, with prominent sandal gap deformity.
Figure 7
Figure 7
Furrowed and creased left sole.
See this image and copyright information in PMC

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