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Angioosteohypertrophic syndrome(KTS)

MedGen UID:
9646
Concept ID:
C0022739
Disease or Syndrome
Synonyms: Angio-osteohypertrophy syndrome; Klippel Trenaunay syndrome; Klippel-Trenaunay-Weber Syndrome; KTS; KTW syndrome; Weber Klippel Trenaunay
SNOMED CT: Klippel Trenaunay syndrome (721105004); Angio-osteohypertrophic syndrome (723991007); Angioosteohypertrophic syndrome (723991007)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Not genetically inherited
MedGen UID:
988794
Concept ID:
CN307044
Finding
Source: Orphanet
clinical entity without genetic inheritance.
 
Monarch Initiative: MONDO:0007864
OMIM®: 149000
Orphanet: ORPHA2346

Definition

Klippel-Trenaunay syndrome is a condition that affects the development of blood vessels, soft tissues (such as skin and muscles), and bones. The disorder has three characteristic features: a red birthmark called a port-wine stain, abnormal overgrowth of soft tissues and bones, and vein malformations.

Most people with Klippel-Trenaunay syndrome are born with a port-wine stain. This type of birthmark is caused by swelling of small blood vessels near the surface of the skin. Port-wine stains are typically flat and can vary from pale pink to deep maroon in color. In people with Klippel-Trenaunay syndrome, the port-wine stain usually covers part of one limb. The affected area may become lighter or darker with age. Occasionally, port-wine stains develop small red blisters that break open and bleed easily.

Klippel-Trenaunay syndrome is also associated with overgrowth of bones and soft tissues beginning in infancy. Usually this abnormal growth is limited to one limb, most often one leg. However, overgrowth can also affect the arms or, rarely, the torso. The abnormal growth can cause pain, a feeling of heaviness, and reduced movement in the affected area. If the overgrowth causes one leg to be longer than the other, it can also lead to problems with walking.

Malformations of veins are the third major feature of Klippel-Trenaunay syndrome. These abnormalities include varicose veins, which are swollen and twisted veins near the surface of the skin that often cause pain. Varicose veins usually occur on the sides of the upper legs and calves. Veins deep in the limbs can also be abnormal in people with Klippel-Trenaunay syndrome. Malformations of deep veins increase the risk of a type of blood clot called a deep vein thrombosis (DVT). If a DVT travels through the bloodstream and lodges in the lungs, it can cause a life-threatening blood clot known as a pulmonary embolism (PE).

Other complications of Klippel-Trenaunay syndrome can include a type of skin infection called cellulitis, swelling caused by a buildup of fluid (lymphedema), and internal bleeding from abnormal blood vessels. Less commonly, this condition is also associated with fusion of certain fingers or toes (syndactyly) or the presence of extra digits (polydactyly). [from MedlinePlus Genetics]

Clinical features

From HPO
Hemangioma
MedGen UID:
5477
Concept ID:
C0018916
Neoplastic Process
A hemangioma is a benign tumor characterized by blood-filled spaces lined by benign endothelial cells. A hemangioma characterized by large endothelial spaces (caverns) is called a cavernous hemangioma (in contrast to a hemangioma with small endothelial spaces, which is called capillary hemangioma).
Syndactyly
MedGen UID:
52619
Concept ID:
C0039075
Congenital Abnormality
Webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. Bony fusions are referred to as "bony" syndactyly if the fusion occurs in a radio-ulnar axis. Fusions of bones of the fingers or toes in a proximo-distal axis are referred to as "symphalangism".
Hand polydactyly
MedGen UID:
510636
Concept ID:
C0158733
Congenital Abnormality
A kind of polydactyly characterized by the presence of a supernumerary finger or fingers.
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.
Finger aplasia
MedGen UID:
1841564
Concept ID:
C5779506
Congenital Abnormality
A developmental defect resulting in the presence of fewer than the normal number of fingers (i.e., aplasia of one or more fingers).
Arteriovenous fistula
MedGen UID:
2041
Concept ID:
C0003855
Anatomical Abnormality
An abnormal connection between an artery and vein.
Hemihypertrophy
MedGen UID:
90701
Concept ID:
C0332890
Congenital Abnormality
Overgrowth of only one side of the body.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Abnormality of blood and blood-forming tissues
MedGen UID:
163092
Concept ID:
C0850715
Finding
An abnormality of the hematopoietic system.
Lymphangioma
MedGen UID:
6153
Concept ID:
C0024221
Neoplastic Process
Lymphangiomas are rare congenital malformations consisting of focal proliferations of well-differentiated lymphatic tissue in multi cystic or sponge like structures. Lymphangioma is usually asymptomatic due to its soft consistency but compression of adjacent structures can be seen due to the mass effect of a large tumor.
Lymphedema
MedGen UID:
6155
Concept ID:
C0024236
Disease or Syndrome
Localized fluid retention and tissue swelling caused by a compromised lymphatic system.
Hyperpigmented nevi and streak
MedGen UID:
812022
Concept ID:
C3805692
Finding
Glaucoma
MedGen UID:
42224
Concept ID:
C0017601
Disease or Syndrome
Glaucoma refers loss of retinal ganglion cells in a characteristic pattern of optic neuropathy usually associated with increased intraocular pressure.

Term Hierarchy

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

Professional guidelines

PubMed

Fereydooni A, Nassiri N
J Vasc Surg Venous Lymphat Disord 2020 May;8(3):482-493. Epub 2020 Feb 20 doi: 10.1016/j.jvsv.2019.12.003. PMID: 32089498
Wang SK, Drucker NA, Gupta AK, Marshalleck FE, Dalsing MC
J Vasc Surg Venous Lymphat Disord 2017 Jul;5(4):587-595. doi: 10.1016/j.jvsv.2016.10.084. PMID: 28624001
Banzic I, Brankovic M, Maksimović Ž, Davidović L, Marković M, Rančić Z
Phlebology 2017 Jul;32(6):371-383. Epub 2016 Aug 9 doi: 10.1177/0268355516664212. PMID: 27511883

Recent clinical studies

Etiology

McCrossan S, Martin S, Hill C
J Craniofac Surg 2021 Jul-Aug 01;32(5):1856-1859. doi: 10.1097/SCS.0000000000007276. PMID: 33235175
Spencer SA, Sorger JI
Semin Pediatr Surg 2020 Oct;29(5):150973. Epub 2020 Sep 19 doi: 10.1016/j.sempedsurg.2020.150973. PMID: 33069292
John PR
Tech Vasc Interv Radiol 2019 Dec;22(4):100634. Epub 2019 Sep 23 doi: 10.1016/j.tvir.2019.100634. PMID: 31864529
Banzic I, Brankovic M, Maksimović Ž, Davidović L, Marković M, Rančić Z
Phlebology 2017 Jul;32(6):371-383. Epub 2016 Aug 9 doi: 10.1177/0268355516664212. PMID: 27511883
Dalal AB, Phadke SR, Pradhan M, Sharda S
Indian J Pediatr 2006 Jul;73(7):609-15. doi: 10.1007/BF02759927. PMID: 16877856

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
Büyükertan M, Söztanacı US, Balcıoğlu HA
Folia Morphol (Warsz) 2022;81(4):1062-1065. Epub 2021 Sep 21 doi: 10.5603/FM.a2021.0091. PMID: 34545558
John PR
Tech Vasc Interv Radiol 2019 Dec;22(4):100634. Epub 2019 Sep 23 doi: 10.1016/j.tvir.2019.100634. PMID: 31864529
Wang SK, Drucker NA, Gupta AK, Marshalleck FE, Dalsing MC
J Vasc Surg Venous Lymphat Disord 2017 Jul;5(4):587-595. doi: 10.1016/j.jvsv.2016.10.084. PMID: 28624001
Dalal AB, Phadke SR, Pradhan M, Sharda S
Indian J Pediatr 2006 Jul;73(7):609-15. doi: 10.1007/BF02759927. PMID: 16877856

Therapy

John PR
Tech Vasc Interv Radiol 2019 Dec;22(4):100634. Epub 2019 Sep 23 doi: 10.1016/j.tvir.2019.100634. PMID: 31864529
Vasani RJ, Khanna D, Singal A
Dermatol Ther 2012 Jul-Aug;25(4):358-75. doi: 10.1111/j.1529-8019.2012.01532.x. PMID: 22950563
Hergesell K, Kröger K, Petruschkat S, Santosa F, Herborn C, Rudofsky G
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Hale EK
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Allergol Immunopathol (Madr) 2001 Jan-Feb;29(1):33-4. doi: 10.1016/s0301-0546(01)79014-3. PMID: 11449534

Prognosis

Büyükertan M, Söztanacı US, Balcıoğlu HA
Folia Morphol (Warsz) 2022;81(4):1062-1065. Epub 2021 Sep 21 doi: 10.5603/FM.a2021.0091. PMID: 34545558
Cohen BA, Turcios NL
Pediatr Clin North Am 2021 Feb;68(1):261-276. doi: 10.1016/j.pcl.2020.09.009. PMID: 33228937
Spencer SA, Sorger JI
Semin Pediatr Surg 2020 Oct;29(5):150973. Epub 2020 Sep 19 doi: 10.1016/j.sempedsurg.2020.150973. PMID: 33069292
Meine JG, Schwartz RA, Janniger CK
Cutis 1997 Sep;60(3):127-32. PMID: 9314616
You CK, Rees J, Gillis DA, Steeves J
Can J Surg 1983 Sep;26(5):399-403. PMID: 6311389

Clinical prediction guides

Wang H, Lin W, Xie C, Yang W, Zhou J, Guo Z
Orphanet J Rare Dis 2023 Sep 12;18(1):288. doi: 10.1186/s13023-023-02857-5. PMID: 37700367Free PMC Article
Fry MV, Williams BK Jr, Kim HJ, Di Nicola M
Retin Cases Brief Rep 2023 Mar 1;17(2):130-133. doi: 10.1097/ICB.0000000000001154. PMID: 33907078
Saleem T, Luke C, Raju S
J Vasc Surg Venous Lymphat Disord 2022 Nov;10(6):1343-1351.e3. Epub 2022 Jun 30 doi: 10.1016/j.jvsv.2022.04.020. PMID: 35779829
Elias AJ, Hand JL, Tollefson MM, Davis DMR
Pediatr Dermatol 2021 Jan;38(1):77-82. Epub 2020 Nov 10 doi: 10.1111/pde.14392. PMID: 33170527
Lee BB, Villavicencio JL
Eur J Vasc Endovasc Surg 2010 May;39(5):646-53. Epub 2010 Feb 21 doi: 10.1016/j.ejvs.2010.01.018. PMID: 20176496

Recent systematic reviews

Nguyen HL, Bonadurer GF 3rd, Tollefson MM
JAMA Dermatol 2018 Jun 1;154(6):661-669. doi: 10.1001/jamadermatol.2018.0002. PMID: 29562060Free PMC Article
Banzic I, Brankovic M, Maksimović Ž, Davidović L, Marković M, Rančić Z
Phlebology 2017 Jul;32(6):371-383. Epub 2016 Aug 9 doi: 10.1177/0268355516664212. PMID: 27511883

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