What is your diagnosis?

Manuela Panteliades Claudia Marcia Resende Silva Bernardo Gontijo About the authors

Abstract:

CLOVES syndrome is a rare, newly described, and relatively unknown syndrome, related to somatic mutations of the PIK3CA gene. Clinical findings include adipose tissue overgrowth, vascular malformations, epidermal nevi, scoliosis, and spinal deformities. This report deals with a characteristic phenotype case, highlighting peculiar cutaneous and radiological changes.

Keywords:
Adipose tissue; Klippel-Trenaunay-Weber Syndrome; Proteus Syndrome; Vascular Malformations

CASE REPORT

A two-year-old child was referred to evaluate the increase in the soft parts in the lower back, left arm, and posterior portion of the lower limbs, which had been present since birth. The patient also present ed flatfeet, epidermal nevi on the right arm, nodular plate with a cystic formation on the left arm, spacing between the first and second toes, capillary malforma tion in the trunk, as well as epispadia and scoliosis of the thoracic-lumbar spine (Figures 1 and 2). Imaging exams (computed tomography of the abdomen and magnetic resonance of the abdomen and right upper limb) revealed confluent and heterogeneous lobes lo cated in the subcutaneous adipose tissue of the abdo men, with a cystic aspect, suggestive of lymphangio ma, an asymmetrical increase in the fat deposit on the retroperitoneal posterior abdominal wall, as well as paravertebral muscles, presence of scoliosis in the tho racic-lumbar spine (Figure 3), and complex vascular malformation in the left arm (Figure 4).

Figure 1 :
Increase in the soft parts of the lumbar region and the pos terior portion of the lower limbs (A), flatfeet, spacing between the first and second toes, and scoliosis of the thoracic-lumbar spine (B)

Figure 2 :
(A) plaque with cystic growth on the left arm; (B) capillary malformation in the trunk; (C) epidermal nevi on the right arm and right cervical region (D)

Figure 3 :
(A) magnetic resonance presenting confluent and heterogeneous lobulated lesions located in the sub cutaneous adipose tissue of the right lower abdo men, presenting a cystic aspect; (B) asymmetric increase of the fat depos it on the retroperitoneal posterior abdominal wall, as well as paravertebral muscles and the presence of scoliosis in the thorac ic-lumbar spine; (C) dif fuse thickness of the sub cutaneous adipose tissue, predominantly found on the thoracic-lumbar spine

Figure 4 :
Magnetic resonance presenting a lobe-shaped expansive lesion in the subcutaneous tissue of the distal third of the arm, extending down to the forearm, on its ulnar surface, compatible with low-flow complex vascular malformation - coronal slice (a) and axial slice (b)

DISCUSSION

The overgrowth syndromes with complex vascular anomalies are rare entities characterized by the association of hypertrophy of one or more regions of the body and multifocal vascular anomalies11 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;143A:2944-58.. The diagnosis and treatment are quite challenging. In the past, patients with skeletal growth were classified as having Proteus syndrome, whereas those with significant vascular abnormalities were diagnosed with Klippel-Trenaunay syndrome22 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.. Recently, the CLOVES syndrome was described and differentiated from other excessive growth disturbances associated with vascular anomalies. The acronym CLOVES (Congenital Lipomatous Overgrowth, Vascular malformation, Epidermal nevi, Scoliosis and spinal deformities) represents the main characteristics of the syndrome: adipose tissue overgrowth, vascular malformations, epidermal nevi, scoliosis, and spinal deformities.11 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;143A:2944-58.,22 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. With only about 20 cases published to date, the syndrome is related to the somatic mutations of the PIK3CA gene in the 3q26.32 chromosome, with consequent activation of the Akt-mTOR pathway. The mTOR protein performs a key regulator role in cell proliferation, growth, and survival.33 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. The activation of this pathway is related to other conditions of overgrowth, such as the Proteus and megalencephaly syndromes.44 Rios JJ, Paria N, Burns DK, Israel BA, Cornelia R, Wise CA, et al. Somatic gain-of-function mutations ?in PIK3CA in patients with macrodactyly. Hum Mol Genet. 2013;22:444-51. The diagnosis is usually clinical, owing to distinct characteristics, with the histopathological exam rarely deemed necessary.55 Bloom J, Upton J 3rd. CLOVES syndrome. J Hand Surg Am. 2013;38:2508-12 The deformities are congenital and represented by lipomatous masses, which result in asymmetric hypertrophy of the trunk, in addition to vascular malformation and epidermal nevi.55 Bloom J, Upton J 3rd. CLOVES syndrome. J Hand Surg Am. 2013;38:2508-12 The involvement of the central nervous system, through non-contiguous abnormalities of the gray and white matter, partial agenesia of the corpus callosum, and ventriculomegaly, has also been reported in prior literature.66 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;146A:2688-90. Muscular-skeletal changes and acral anomalies include legs with an uneven length, chondromalacia patellae, scoliosis, large hands and legs, and an increase in the distance between the first and second toes. There are no associated cardiovascular, gastrointestinal, or hematopoietic anomalies.55 Bloom J, Upton J 3rd. CLOVES syndrome. J Hand Surg Am. 2013;38:2508-12 The treatment is similar to other forms of overgrowth, with surgical reconstruction often recommended.77 Klein S, Stroberg A, Ghahremani S, Martinez-Agosto JA. Phenotypic progression of skeletal anomalies in CLOVES syndrome. Am J Med Genet A. 2012;158A:1690-5.

  • Financial Support: None.
  • *
    Work performed at the Hospital das Clínicas da Universidade Federal de Minas Gerais (HC-UFMG) - Belo Horizonte (MG), Brazil.

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;143A:2944-58.
  • 2
    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.
  • 3
    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.
  • 4
    Rios JJ, Paria N, Burns DK, Israel BA, Cornelia R, Wise CA, et al. Somatic gain-of-function mutations ?in PIK3CA in patients with macrodactyly. Hum Mol Genet. 2013;22:444-51.
  • 5
    Bloom J, Upton J 3rd. CLOVES syndrome. J Hand Surg Am. 2013;38:2508-12
  • 6
    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;146A:2688-90.
  • 7
    Klein S, Stroberg A, Ghahremani S, Martinez-Agosto JA. Phenotypic progression of skeletal anomalies in CLOVES syndrome. Am J Med Genet A. 2012;158A:1690-5.

Publication Dates

  • Publication in this collection
    May-Jun 2016

History

  • Received
    07 Apr 2016
  • Accepted
    17 May 2016
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