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CLOVES syndrome

MedGen UID:
442876
Concept ID:
C2752042
Disease or Syndrome
Synonyms: CLOVE SYNDROME; CLOVES; Congenital lipomatous overgrowth, vascular malformations, and epidermal nevi; CONGENITAL LIPOMATOUS OVERGROWTH, VASCULAR MALFORMATIONS, AND EPIDERMAL NEVI, SOMATIC; CONGENITAL LIPOMATOUS OVERGROWTH, VASCULAR MALFORMATIONS, EPIDERMAL NEVI, AND SKELETAL/SPINAL ABNORMALITIES
SNOMED CT: Congenital lipomatous overgrowth, vascular malformation, epidermal nevi, skeletal anomaly syndrome (719475006); CLOVE syndrome (719475006); CLOVES syndrome (719475006)
Modes of inheritance:
Not genetically inherited
MedGen UID:
988794
Concept ID:
CN307044
Finding
Source: Orphanet
clinical entity without genetic inheritance.
 
Gene (location): PIK3CA (3q26.32)
 
Monarch Initiative: MONDO:0013038
OMIM®: 612918
Orphanet: ORPHA140944

Disease characteristics

Excerpted from the GeneReview: PIK3CA-Related Overgrowth Spectrum
PIK3CA-related overgrowth spectrum (PROS) encompasses a range of clinical findings in which the core features are congenital or early-childhood onset of segmental/focal overgrowth with or without cellular dysplasia. Prior to the identification of PIK3CA as the causative gene, PROS was separated into distinct clinical syndromes based on the tissues and/or organs involved (e.g., MCAP [megalencephaly-capillary malformation] syndrome and CLOVES [congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies] syndrome). The predominant areas of overgrowth include the brain, limbs (including fingers and toes), trunk (including abdomen and chest), and face, all usually in an asymmetric distribution. Generalized brain overgrowth may be accompanied by secondary overgrowth of specific brain structures resulting in ventriculomegaly, a markedly thick corpus callosum, and cerebellar tonsillar ectopia with crowding of the posterior fossa. Vascular malformations may include capillary, venous, and less frequently, arterial or mixed (capillary-lymphatic-venous or arteriovenous) malformations. Lymphatic malformations may be in various locations (internal and/or external) and can cause various clinical issues, including swelling, pain, and occasionally localized bleeding secondary to trauma. Lipomatous overgrowth may occur ipsilateral or contralateral to a vascular malformation, if present. The degree of intellectual disability appears to be mostly related to the presence and severity of seizures, cortical dysplasia (e.g., polymicrogyria), and hydrocephalus. Many children have feeding difficulties that are often multifactorial in nature. Endocrine issues affect a small number of individuals and most commonly include hypoglycemia (largely hypoinsulinemic hypoketotic hypoglycemia), hypothyroidism, and growth hormone deficiency. [from GeneReviews]
Authors:
Ghayda Mirzaa  |  John M Graham  |  Kim Keppler-Noreuil   view full author information

Clinical features

From HPO
Lipoma
MedGen UID:
44173
Concept ID:
C0023798
Neoplastic Process
Benign neoplasia derived from lipoblasts or lipocytes of white or brown fat. May be angiomatous or hibernomatous.
Nephroblastoma
MedGen UID:
10221
Concept ID:
C0027708
Neoplastic Process
The presence of a nephroblastoma, which is a neoplasm of the kidney that primarily affects children.
Renal hypoplasia
MedGen UID:
120571
Concept ID:
C0266295
Congenital Abnormality
Hypoplasia of the kidney.
Congenital macrodactylia
MedGen UID:
78564
Concept ID:
C0265552
Congenital Abnormality
PIK3CA-related overgrowth spectrum (PROS) encompasses a range of clinical findings in which the core features are congenital or early-childhood onset of segmental/focal overgrowth with or without cellular dysplasia. Prior to the identification of PIK3CA as the causative gene, PROS was separated into distinct clinical syndromes based on the tissues and/or organs involved (e.g., MCAP [megalencephaly-capillary malformation] syndrome and CLOVES [congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies] syndrome). The predominant areas of overgrowth include the brain, limbs (including fingers and toes), trunk (including abdomen and chest), and face, all usually in an asymmetric distribution. Generalized brain overgrowth may be accompanied by secondary overgrowth of specific brain structures resulting in ventriculomegaly, a markedly thick corpus callosum, and cerebellar tonsillar ectopia with crowding of the posterior fossa. Vascular malformations may include capillary, venous, and less frequently, arterial or mixed (capillary-lymphatic-venous or arteriovenous) malformations. Lymphatic malformations may be in various locations (internal and/or external) and can cause various clinical issues, including swelling, pain, and occasionally localized bleeding secondary to trauma. Lipomatous overgrowth may occur ipsilateral or contralateral to a vascular malformation, if present. The degree of intellectual disability appears to be mostly related to the presence and severity of seizures, cortical dysplasia (e.g., polymicrogyria), and hydrocephalus. Many children have feeding difficulties that are often multifactorial in nature. Endocrine issues affect a small number of individuals and most commonly include hypoglycemia (largely hypoinsulinemic hypoketotic hypoglycemia), hypothyroidism, and growth hormone deficiency.
Sandal gap
MedGen UID:
374376
Concept ID:
C1840069
Finding
A widely spaced gap between the first toe (the great toe) and the second toe.
Venous malformation
MedGen UID:
754284
Concept ID:
C2937220
Congenital Abnormality
A vascular malformation resulting from a developmental error of venous tissue composed of dysmorphic channels lined by flattened endothelium and exhibiting slow turnover. A venous malformation may present as a blue patch on the skin ranging to a soft blue mass. Venous malformations are easily compressible and usually swell in thewhen venous pressure increases (e.g., when held in a dependent position or when a child cries). They may be relatively localized or quite extensive within an anatomic region.
Abnormality of cardiovascular system morphology
MedGen UID:
892473
Concept ID:
C4049796
Congenital Abnormality
Any structural anomaly of the heart and great vessels.
Lower limb asymmetry
MedGen UID:
44089
Concept ID:
C0023221
Finding
A difference in length or diameter between the left and right leg.
Hemihypertrophy
MedGen UID:
90701
Concept ID:
C0332890
Congenital Abnormality
Overgrowth of only one side of the body.
Overgrowth
MedGen UID:
376550
Concept ID:
C1849265
Finding
Excessive postnatal growth which may comprise increased weight, increased length, and/or increased head circumference.
Tethered cord
MedGen UID:
36387
Concept ID:
C0080218
Disease or Syndrome
During normal embryological development, the spinal cord first occupies the entire length of the vertebral column but goes on to assume a position at the level of L1 due to differential growth of the conus medullaris and the vertebral column. The filum terminale is a slender, threadlike structure that remains after the normal regression of the distal embryonic spinal cord and attaches the spinal cord to the coccyx. A tethered cord results if there is a thickened rope-like filum terminale which anchors the cord at the level of L2 or below, potentially causing neurologic signs owing to abnormal tension on the spinal cord.
Spinal dysraphism
MedGen UID:
807335
Concept ID:
CN218435
Finding
A heterogeneous group of congenital spinal anomalies that result from defective closure of the neural tube early in fetal life.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Cranial hyperostosis
MedGen UID:
318629
Concept ID:
C1832451
Finding
Excessive growth of the bones of cranium, i.e., of the skull.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Webbed neck
MedGen UID:
113154
Concept ID:
C0221217
Congenital Abnormality
Pterygium colli is a congenital skin fold that runs along the sides of the neck down to the shoulders. It involves an ectopic fibrotic facial band superficial to the trapezius muscle. Excess hair-bearing skin is also present and extends down the cervical region well beyond the normal hairline.
Facial asymmetry
MedGen UID:
266298
Concept ID:
C1306710
Finding
An abnormal difference between the left and right sides of the face.
Capillary malformation
MedGen UID:
90955
Concept ID:
C0340803
Congenital Abnormality
Capillary malformations are a form of vascular malformation that are present from birth, tend to grow with the individual, do not regress spontaneously, and show normal rates of endothelial cell turnover. Capillary malformations are distinct from capillary hemangiomas (602089), which are highly proliferative lesions that appear shortly after birth and show rapid growth, slow involution, and endothelial hypercellularity (Spring and Bentz, 2005; Legiehn and Heran, 2006).

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for CLOVES syndrome in Orphanet.

Professional guidelines

PubMed

Flores-Sarnat L, Sarnat HB
Handb Clin Neurol 2015;132:9-25. doi: 10.1016/B978-0-444-62702-5.00002-0. PMID: 26564069
Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ, Sapp JC, Alomari A, Ezaki M, Dobyns W, Biesecker LG
Am J Med Genet A 2015 Feb;167A(2):287-95. Epub 2014 Dec 31 doi: 10.1002/ajmg.a.36836. PMID: 25557259Free PMC Article
Dasgupta R, Fishman SJ
Semin Pediatr Surg 2014 Aug;23(4):216-20. Epub 2014 Jul 15 doi: 10.1053/j.sempedsurg.2014.07.003. PMID: 25241101

Recent clinical studies

Etiology

Alzahrani AS, Alswailem M, Alghamdi B, Rafiullah R, Aldawish M, Al-Hindi H
Endocrine 2022 Feb;75(2):478-486. Epub 2021 Oct 12 doi: 10.1007/s12020-021-02895-8. PMID: 34637071
Martinez-Lopez A, Salvador-Rodriguez L, Montero-Vilchez T, Molina-Leyva A, Tercedor-Sanchez J, Arias-Santiago S
Curr Opin Pediatr 2019 Dec;31(6):747-753. doi: 10.1097/MOP.0000000000000812. PMID: 31693582
Flores-Sarnat L, Sarnat HB
Handb Clin Neurol 2015;132:9-25. doi: 10.1016/B978-0-444-62702-5.00002-0. PMID: 26564069
Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ, Sapp JC, Alomari A, Ezaki M, Dobyns W, Biesecker LG
Am J Med Genet A 2015 Feb;167A(2):287-95. Epub 2014 Dec 31 doi: 10.1002/ajmg.a.36836. PMID: 25557259Free PMC Article
Alomari AI, Burrows PE, Lee EY, Hedequist DJ, Mulliken JB, Fishman SJ
J Thorac Cardiovasc Surg 2010 Aug;140(2):459-63. Epub 2010 May 27 doi: 10.1016/j.jtcvs.2010.04.023. PMID: 20537357

Diagnosis

Escobar K, Pandher K, Jahnke MN
Dermatol Clin 2022 Oct;40(4):425-433. Epub 2022 Sep 16 doi: 10.1016/j.det.2022.06.005. PMID: 36243429
Martinez-Lopez A, Salvador-Rodriguez L, Montero-Vilchez T, Molina-Leyva A, Tercedor-Sanchez J, Arias-Santiago S
Curr Opin Pediatr 2019 Dec;31(6):747-753. doi: 10.1097/MOP.0000000000000812. PMID: 31693582
Martinez-Lopez A, Blasco-Morente G, Perez-Lopez I, Herrera-Garcia JD, Luque-Valenzuela M, Sanchez-Cano D, Lopez-Gutierrez JC, Ruiz-Villaverde R, Tercedor-Sanchez J
Clin Genet 2017 Jan;91(1):14-21. Epub 2016 Aug 3 doi: 10.1111/cge.12832. PMID: 27426476
Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ, Sapp JC, Alomari A, Ezaki M, Dobyns W, Biesecker LG
Am J Med Genet A 2015 Feb;167A(2):287-95. Epub 2014 Dec 31 doi: 10.1002/ajmg.a.36836. PMID: 25557259Free PMC Article
Bloom J, Upton J 3rd
J Hand Surg Am 2013 Dec;38(12):2508-12. Epub 2013 Oct 23 doi: 10.1016/j.jhsa.2013.08.120. PMID: 24161472

Therapy

Garreta Fontelles G, Pardo Pastor J, Grande Moreillo C
Br J Clin Pharmacol 2022 Aug;88(8):3891-3895. Epub 2022 Feb 21 doi: 10.1111/bcp.15270. PMID: 35146800
Morin G, Degrugillier-Chopinet C, Vincent M, Fraissenon A, Aubert H, Chapelle C, Hoguin C, Dubos F, Catteau B, Petit F, Mezel A, Domanski O, Herbreteau G, Alesandrini M, Boddaert N, Boutry N, Broissand C, Han TK, Branle F, Sarnacki S, Blanc T, Guibaud L, Canaud G
J Exp Med 2022 Mar 7;219(3) Epub 2022 Jan 26 doi: 10.1084/jem.20212148. PMID: 35080595Free PMC Article
Martinez-Lopez A, Salvador-Rodriguez L, Montero-Vilchez T, Molina-Leyva A, Tercedor-Sanchez J, Arias-Santiago S
Curr Opin Pediatr 2019 Dec;31(6):747-753. doi: 10.1097/MOP.0000000000000812. PMID: 31693582
Venot Q, Blanc T, Rabia SH, Berteloot L, Ladraa S, Duong JP, Blanc E, Johnson SC, Hoguin C, Boccara O, Sarnacki S, Boddaert N, Pannier S, Martinez F, Magassa S, Yamaguchi J, Knebelmann B, Merville P, Grenier N, Joly D, Cormier-Daire V, Michot C, Bole-Feysot C, Picard A, Soupre V, Lyonnet S, Sadoine J, Slimani L, Chaussain C, Laroche-Raynaud C, Guibaud L, Broissand C, Amiel J, Legendre C, Terzi F, Canaud G
Nature 2018 Jun;558(7711):540-546. Epub 2018 Jun 13 doi: 10.1038/s41586-018-0217-9. PMID: 29899452Free PMC Article
Alomari AI, Burrows PE, Lee EY, Hedequist DJ, Mulliken JB, Fishman SJ
J Thorac Cardiovasc Surg 2010 Aug;140(2):459-63. Epub 2010 May 27 doi: 10.1016/j.jtcvs.2010.04.023. PMID: 20537357

Prognosis

Yan W, Zhang B, Wang H, Mo R, Jiang X, Qin W, Ma L, Lin Z
Hereditas 2021 Jun 1;158(1):18. doi: 10.1186/s41065-021-00184-y. PMID: 34074347Free PMC Article
Reis J 3rd, Alomari AI, Trenor CC 3rd, Adams DM, Fishman SJ, Spencer SA, Shaikh R, Lillis AP, Surnedi MK, Chaudry G
J Vasc Surg Venous Lymphat Disord 2018 Jul;6(4):511-516. doi: 10.1016/j.jvsv.2018.01.015. PMID: 29909856
Flores-Sarnat L, Sarnat HB
Handb Clin Neurol 2015;132:9-25. doi: 10.1016/B978-0-444-62702-5.00002-0. PMID: 26564069
Bloom J, Upton J 3rd
J Hand Surg Am 2013 Dec;38(12):2508-12. Epub 2013 Oct 23 doi: 10.1016/j.jhsa.2013.08.120. PMID: 24161472
Alomari AI, Orbach DB, Mulliken JB, Bisdorff A, Fishman SJ, Norbash A, Alokaili R, Lord DJ, Burrows PE
AJNR Am J Neuroradiol 2010 Oct;31(9):1608-12. Epub 2010 Jul 22 doi: 10.3174/ajnr.A2167. PMID: 20651014Free PMC Article

Clinical prediction guides

Yan W, Zhang B, Wang H, Mo R, Jiang X, Qin W, Ma L, Lin Z
Hereditas 2021 Jun 1;158(1):18. doi: 10.1186/s41065-021-00184-y. PMID: 34074347Free PMC Article
Rössler J, Baselga E, Davila V, Celis V, Diociaiuti A, El Hachem M, Mestre S, Haeberli D, Prokop A, Hanke C, Loichinger W, Quéré I, Baumgartner I, Niemeyer CM, Kapp FG
Pediatr Blood Cancer 2021 Aug;68(8):e28936. Epub 2021 Feb 13 doi: 10.1002/pbc.28936. PMID: 33580918
de Grazia R, Giordano C, Cossio L, Downey C, Delucchi Á, Kramer D
Rev Chil Pediatr 2019 Dec;90(6):662-667. doi: 10.32641/rchped.v90i6.1025. PMID: 32186590
Flores-Sarnat L, Sarnat HB
Handb Clin Neurol 2015;132:9-25. doi: 10.1016/B978-0-444-62702-5.00002-0. PMID: 26564069
Alomari AI
Clin Dysmorphol 2009 Jan;18(1):1-7. doi: 10.1097/MCD.0b013e328317a716. PMID: 19011570

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