Sandbox:OhGodWhy

# Overview
 defined as two or more vascular malformations found in one lesion
- high flow lesions

# Classification

## Classification of Vascular Malformations

## Tables

# Vascular Tumors

## Benign vascular tumors 1

### Infantile hemangioma / Hemangioma of infancy
- Most common tumor of infancy. Usually appearing after birth, infantile hemangiomas undergo a period of proliferation in few weeks after birth followed by regression and involution in first year of life. Superficial lesions appear as red or strawberry colored nodules, papules, or plaques while deeper hemangiomas are typically bluish or skin colored. Mixed tumors, involving both epidermis and deeper structures, may display characteristics of both. They may also be classified as focal, that appear in a specific anatomical area, and segmental that shows varied pattern of growth following developmental growth regions. Segmental type is often associated with other developmental abnormalities.
- Rarely, infantile hemangioms can cause life-threatening complications such as congestive cardiac failure, respiratory difficulty and respiratory compromise, and loss of vision. There may also be long-term sequela including permanent disfigurement and scarring. If lesions are multiple, there is an increased risk of visceral involvement. There may be an association with certain syndromes such as PHACE syndrome.
- Some studies have indicated autosomal-dominant and maternal patterns of inheritance. Some studies suggest that environmental factors play the key role. Some risk factors that have been identified in association with infantile hemangioma include female gender, preterm birth, low weight at birth, increasing maternal age ta birth, placenta previa, pre-eclampsia, progesterone use by mother, and Caucasian race.
- THE diagnosis is made clinically and a thorough investigation should be carried out for visceral hemangiomas and other associative abnormalities if suspicion arises. Majority of these lesions do not require any treatment but treatment is indicated if there is risk for complications such as visual or respiratory involvement. Elective treatment is also offered to prevent disfigurement or scarring. Recently there have been an increased usage of oral beta-blockers such as timolol over systemic glucocorticoids because of higher efficacy.  Vincristine and interferon alpha have been used in some high risk hemangiomas but carry the risk of severe complications. Visceral hemangioms may require embolization or surgery if they do not respond to systemic therapy. Laser therapy especially PDL is another modality used in cases of hemangioms unresponsive to medication.
- To learn more about infantile hemagioma click here.

### Congenital hemangioma
- Rare tumor that arises in utero and presents as fully developed lesion at birth. Following birth they can regress completely, partially or not at all. So they can be classified as Rapidly involuting (RICH), Non-involuting (NICH), Partially involuting (PICH).
Rapidly involuting (RICH)
This fast flow tumor can be detected in utero and appears as raised gray single lesions with dilated veins, telangiectasias and a halo at birth. This tumor may be complicated by thrombocytopenia and congestive cardiac failure due to its high-flow nature. Tumor typically regresses spontaneously in 1 to 2 years of life. Sometimes it can occur in liver where it follows the same pattern of involution as that of skin.
Non-involuting (NICH)
Fast flow tumor that presents as well defined, plaque like lesion with pink to purple color, telangiectasias and pale borders. Typically remains stable but there have been some reports of growth and expansion.
Partially involuting (PICH)
These lesions start involution as RICH but become stable over time and persist as NICH.
- Rapidly involuting (RICH)
This fast flow tumor can be detected in utero and appears as raised gray single lesions with dilated veins, telangiectasias and a halo at birth. This tumor may be complicated by thrombocytopenia and congestive cardiac failure due to its high-flow nature. Tumor typically regresses spontaneously in 1 to 2 years of life. Sometimes it can occur in liver where it follows the same pattern of involution as that of skin.
- This fast flow tumor can be detected in utero and appears as raised gray single lesions with dilated veins, telangiectasias and a halo at birth. This tumor may be complicated by thrombocytopenia and congestive cardiac failure due to its high-flow nature. Tumor typically regresses spontaneously in 1 to 2 years of life. Sometimes it can occur in liver where it follows the same pattern of involution as that of skin.
- Non-involuting (NICH)
Fast flow tumor that presents as well defined, plaque like lesion with pink to purple color, telangiectasias and pale borders. Typically remains stable but there have been some reports of growth and expansion.
- Fast flow tumor that presents as well defined, plaque like lesion with pink to purple color, telangiectasias and pale borders. Typically remains stable but there have been some reports of growth and expansion.
- Partially involuting (PICH)
These lesions start involution as RICH but become stable over time and persist as NICH.
- These lesions start involution as RICH but become stable over time and persist as NICH.
- Somatic mutations in GNAQ/GNA11 are thought to cause the congenital hemangioma. GNAQ and its paralogue GNA11 function in intracellular signaling pathways as Gq alpha subunit.
- Diagnosis is usually clinical but imaging techniques such as MRI, CT scan, contrast-enhanced ultrasound and later biopsy can be considered if required. Surgical excision should be considered in case of complications, NICH and PICH.

### Tufted angioma
- Benign tumor that is characterized by dense clumps of endothelial cells and capillaries located in dermis. Most lesions appear in adolescence but some can manifest at birth or late in adulthood. Clinical presentation varies but majority of lesions appear as solitary stained area or elevation that later forms red-purple or dusky red plaque while some lesions appear as firm nodules. Lesions are usually solitary, asymptomatic but tender with occasional painful episodes and located on trunk and neck in majority of the cases. Some cases of multi-focal tufted angiomas have also been reported.
- Tufted angioma can be associated with Kasabach-Merritt phenomenon.
- Somatic activating GNA14 c.614A>T (p.Gln205Leu) mutations have been found in some tufted angiomas. These mutations may cause the cell growth to be growth-factor independent by up-regulating the MAPK pathway.
- Imaging such as MRI and ultrasound can add into clinical diagnosis to differentiate tufted angioma from similar lesions such as Kaposi sarcoma, kaposiform hemangioendothelioma and infantile hemangioma. Biopsy and histopathological studies are sometimes required for accurate diagnosis. Surgical excision is the treatment modality but some recommend to only observe the lesions due to its slow growth and possible remission. Other therapies include radiation beam therapy, cryosurgery, corticosteroids and pulsed laser therapy. Vincristine and embolization has been used with success in angiomas associated with Kasabach-Merritt phenomenon.

### Spindle-cell hemangioma
- Rare benign tumor that manifests as solitary or multiple nodules confined to dermis and subcutaneous tissues in almost all of the cases. Histopathologically it appears as solid areas that are cellular and consist of spindle cells seen attached to vessel walls, and cavernous spaces that can be thrombosed. Size may increase over time and patient usually complains of swelling and pain. The nodules or masses can be mobile and elastic or can be firm and immobile.
- Somatic mutations in IDH1 and IDH2 have been found to be present in 70% of spindle-cell hemangiomas. IDH1 and IDH2 are important enzymes in cell energy cycles (-ketoglutarate and NADPH generation).
- Diagnosis often requires biopsy and imaging studies such as MRI to ascertain the extent of the tumor. Local excision is the treatment modality of choice with excellent prognosis in majority of the cases although recurrence is very common.

### Epithelioid hemangioma
- Rare benign tumor that typically presents as solitary painful nodule on head and neck. Penis is an atypical location. They can involve skin, bone and soft tissues. Histopathologically these lesions are characterized by presence of endothelial cells that resemble epithelial cells with evidence of proliferation such as large nuclei and prominent nucleoli, and often inflammatory infiltrates. Vessels are typically well-formed. Nuclear atypia is absent.
- FOS gene rearrangements such as  ZFP36-FOSB fusions are found to be present in one third of epithelioid hemangioma in a study. It encodes a transcription factors that causes over-expression of vascular endothelial growth factor-D (VEGF-D).
- Diagnosis requires biopsy to determine characteristic histopathological features. Imaging techniques such as MRI can useful. Bone tumors often require surgery for accurate diagnosis. Surgical excision has been used in majority of cases. Other treatment modalities include radiotherapy and embolization. Recently chemoembolization and microwave ablation in combination have been used with success.

### Pyogenic granuloma
- Also called as lobular capillary hemangioma, this common vascular lesion typically manifests as single, localized nodules on gingiva with sessile base but large lesions often present as lobulated or pediculated . Majority of the lesions are <2 cm in diameter and color of the lesion depending on vascularity varies from pink to purple. It can found anywhere on skin and mucous membranes such as lips, tongues, palate, and on atypical locations such asperiungual or gastrointestinal tract but gingiva is the typical location. Majority of the patients present with profuse bleeding. Others complain of painless mass, swelling, obstructive or interference related symptoms.
- Trauma or chronic irritation have been cited as the most common causes but it can arise due to multiple other factors such as medications, viral infections such as herpes virus type 1, Orf virus and/or human papilloma virus type 2, and BRAF mutations or use of BRAF inhibitors that can cause multiple, disseminated lesions. Medications that have been implicated in development of this lesion include oral contraceptives, retinoids, gefitinib, cabecitabine, and afatinib, BRAF inhibitors such as vemurafenib or encorafenib, and rituximab. Mutations in BRAF/RAS/GNA14 have all been associated with pyogenic granuloma, BRAF c.1799T>A has been recently described as one of the major mutations associated.
- The diagnosis is made by clinical features and then confirmed by histopatholgical features. Current standard of care is surgical excision. Other treatment modalities include curettage, electrocautery, radiosurgery, cryosurgery, sclerotherapy, or laser treatment. Topical or oral beta-blockers timolol or propranolol and topical imiquimod have also been successful.

### Hobnail hemangioma
- Benign tumor that typically presents as solitary growth with often, but not always, tagetoid appearance of a central papule and peripheral brown ring that may or may not disappear over time. Characteristic histopathological feature include plump endothelial cells that line ectatic and irregular vessels, and project into lumina like hobnails. Deeper dermis shows vessels dissecting collagen fibers. Majority of the lesions are fund on trunk and extremities with head and neck, and oral cavity as uncommon locations. Patient may present with pain, or an asymptomatic growing lesion.

## Locally aggressive or borderline vascular tumors

### Kaposiform hemangioendothelioma
- Locally Aggressive tumor that originates on skin and occurs primarily in childhood. It is characterized by a single or multiple masses with following characteristics:
Deep reddish-purple color
Shiny, firm texture
Warm to the touch
Swollen and painful
- Deep reddish-purple color
- Shiny, firm texture
- Warm to the touch
- Swollen and painful
- May be complicated by Kasabach-Merritt phenomenon (KMP), characterized by consumption coagulopathy, thrombocytopenia, and hemolytic anemia. Typical features also include low fibrinogen and elevated D-dimers.
- Somatic activating GNA14 c.614A>T (p.Gln205Leu) mutations have been found in some KHE.
- Invasion of bone, retroperitoneum, and mediastinum has occured in some cases but no case of metastasis has been reported yet. 
- Diagnostic work up may include blood tests, biopsy, contrast enhanced ultrasound and MRI or CT scan imaging.
- Treatment Options include steroid, vincristine, interferon alpha, anti-platelet agents, sirolimus-containing therapies and surgery.

### Retiform hemangioendothelioma
- First described in 1994 as a form of low grade angiosarcoma, Retiform hemangioendothelioma commonly presents as a slow growing asymptomatic solitary nodule or plaque on distal extremities in 2nd-4th decade of life.
- Must be differentiated from Angiosarcoma.
- High level of local recurrence but very low potential for metastasis.
- Diagnostic work up includes histopathological studies, that shows arborizing blood vessels are arranged in retiform pattern , and MRI.
- Surgery is the treatment of choice, though 2/3rd cases recur. Adjuvant radiotherapy and ddjuvant chemotherapy with recombinant interferon alpha and low dose cisplatin have also been reported in selected cases. 

### Papillary intralymphatic angioendothelioma (PILA), Dabska tumor
- First described in 1969 by Dabska,this rare vascular neoplasm generally occurs in soft tissues but can also occur in bone. They usually appear as painless inflammatory irregular or nodular lesions below the skin surface.
- The distinctive feature on histopathology is the intravascular growth of well-differentiated endothelial cells presenting as a matchstick columnar configuration.
- They are locally aggressive but rarely metastasize. Locally recurrence after surgery is very common.
- Diagnostic studies may include histopathological studies, fine needle aspiration, MRI and Ct scan.
- Wide local excision is the treatment of choice. However any combination of steroids, chemotherapy, radiation therapy, and invasive procedures can be used to treat this tumor.

### Composite hemangioendothelioma
- A rare vascular neoplasms, characterized by an admixture of benign, low-grade malignant, and malignant vascular components, the ratio of each component can vary. They can occur in any age group.
- They occur predominantly as long-standing lesions in the dermis and subcutis of the extremities, but can also occur at other sites, including the oral cavity and in viscera such as kidney and spleen.
- It may recur locally and has the potential to metastasize. Recurrence was found to be in 8/10 cases in some studies. 
- Diagnostic work up must include biopsy because of heterogeneity of lesions and it must be differentiated from other vascular tumors.
- Surgical excision is the treatment of choice although some patients have been treated with interferon and electron beams.

### Pseudomyogenic hemangioendothelioma
- A locally aggressive tumor with endothelial differentiation that usually presents as multiple asymptomatic discontinuous lesions, often at extremities.
- SERPINE1-FOSB fusions are characteristic that result in over-expression of truncated form of FOSB. FBJ murine osteosarcoma viral oncogene homolog B, also known as Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog B, FOSB or FosB, is a protein that, in humans have been implicated as regulators of cell proliferation, differentiation, and transformation.
- It may mimic epithelioid sarcoma on histology but metastasis is very rare and prognosis is excellent.
- Diagnostic work up includes X-ray, MRI, CT scan and biopsy of the lesion.
- Excision is the typical treatment but chemotherapeutic agents including gemcitabine/taxane and mammalian target of rapamycin inhibitor , mTOR inhibitors such as sirolimus , VEGFR1-4/PDGFRA inhibitors such as telatinib  have been used with success in various studies.

### Polymorphous hemangioendothelioma
- A rare vascular neoplasm, Polymorphous hemangioendothelioma occurs in lymph nodes, but a few cases have been found in extra-nodal sites such as the mediastinum, spinal cord, and liver. It is a very rare cause of persistent lymphadenopathy. The data on natural history and clinical presentation is limited due to very few number of cases reported. 
- Characterized by a polymorphous blend of solid, primitive vascular and angiomatous areas in varied proportions on microscopic examination.
- Diagnotic work up includes histopathological examination, MRI and Ct scan.
- Wide local excision has been used for treatment, with radiation therapy in case of recurrence.

### Kaposi sarcoma
- An AIDS-associated vascular malignancy that usually presents as mucocutaneous lesions  but can also occur in viscera such as lungs. It can remain confined to skin but widespread visceral involvement may occur.
- There are three known variants
One variant occurs spontaneously in Jewish and Italian males in Europe and the United States.
Another more aggressive variant is endemic in young children is endemic in Africa.
A third form occurs in about 0.04% of kidney transplant patients. There is also a high incidence in AIDS patients. HHV-8 is the suspected cause.
- One variant occurs spontaneously in Jewish and Italian males in Europe and the United States.
- Another more aggressive variant is endemic in young children is endemic in Africa.
- A third form occurs in about 0.04% of kidney transplant patients. There is also a high incidence in AIDS patients. HHV-8 is the suspected cause.
- To learn more about KS, click here.

## Malignant vascular tumors

### Angiosarcoma
- Angiosarcoma(AS) is malignancy that presents with a very heterogeneous distribution in the human body with aggressive clinical course, and may appear in multiple locations, from breast to liver or skin.
- Associated with MYC gene amplification and protein overexpression. Myc is a family of regulator genes and proto-oncogenes that code for transcription factors.
- Complete surgical excision and radiotherapy are the main treatments, with a minor role of chemotherapy.
- To learn more about angiosarcoma click here.

### Epithelioid hemangioendothelioma
- A rare vascular tumor, described for the first time in 1975 by Dail and Liebow,that usually affects lung, liver and bones, although may occur many other sites in body including head and neck, breasts and lymph nodes.
- Usually Asymptomatic but patient may present with respiratory symptoms, bone pains or other symptoms depending on the site of the tumor.
- Majority are characterized by a reciprocal t(1;3)(p36;q25) translocation. The t(1;3) results in fusion of a gene known as WWTR1 (or TAZ) to CAMTA1. These genes code for transcription factors.
- Imaging is crucial in forming both diagnosis and management plan. Recognition of the expression of vascular markers (Fli-1 and CD31 are endothelial-specific markers), and the microscopic evidence of vascular differentiation is of primary importance as well.
- Surgery has been used as primary treatment modality depending upon the location of the tumor, with radiotherapy being used in some cases.

# Vascular malformations

## Simple vascular malformations

### Capillary malformations (CM)
- Also called "salmon patch" , angel kiss, stork bite, this common anomaly presents as single or multiple blanchable, pink-red patches with poorly defined borders in newborn infants. It may affect up to 60% of new born infants.
- Typically are found at the nape of the neck , on the forehead between the eyebrows or on the eyelids. Although asymptomatic, they often become more noticeable during crying or temperature changes.
- Fades within one to two years, though some lesions can persist on the back of the neck. No treatment is needed except when asked by the patient.
- Imaging studies are recommended to evaluate for underlying spinal dysraphism if lumbosacral nevus simplex is present with another lumbosacral abnormality such as dermal sinus or pit, lipoma, patch of hypertrichosis, or deviated gluteal cleft.
- "A vascular malformation of developmental origin characterized pathologically by ectasia of superficial dermal capillaries, and clinically by persistent macular erythema." They occur on face for majority of times and may vary from pale pink to deep red or purple, ranging from few millimeters to centimeters in diameter. Lesions are usually flat, are not painful and do not regress spontaneously.
- Can be classified as follows:
Nonsyndromic CM
CM with CNS and/or ocular anomalies (Sturge-Weber syndrome)
CM with bone and/or soft tissues overgrowth
Diffuse CM with overgrowth (DCMO)
- Nonsyndromic CM
- CM with CNS and/or ocular anomalies (Sturge-Weber syndrome)
- CM with bone and/or soft tissues overgrowth
- Diffuse CM with overgrowth (DCMO)
- Usually occur as sporadic isolated lesions, following the embryonic vasculature of the face. Majority of lesions are caused by somatic mutations in GNAQ (Guanine nucleotide-binding protein G(q) subunit alpha) and its paralogue GNA 11. Somatic activating mutation in  GNAQ c.548G>A, p.Arg183Gln has been demonstrated in majority of lesions. A novel GNAQ, c.547C>G, p.Arg183Gly variant has also been found to be associated with some lesions.
- May be associated with other abnormalities including glaucoma, and soft tissue and bone overgrowth and with various syndromes including Sturge-Weber syndrome, Klippel-Trenaunay syndrome, Parkes-Weber syndrome, Servelle-Martorell syndrome, Proteus syndrome, CLOVES syndrome, Bannayan-Riley-Ruvalcaba syndrome, Capillary malformation-arteriovenous malformation syndrome, Macrocephaly-capillary malformation syndrome, Microcephaly-capillary malformation syndrome, Beckwith-Wiedemann syndrome.
- Diagnosis is mainly clinical depending upon history and examination. New born screening for other congenital and genetic anomalies may be indicated including urgent ophthalmology review and a brain MRI.
- The pulsed dye laser (PDL) treatment is considered to be the gold standard. Surgery is considered when PWS is associated with bone and soft tissues overgrowth.
- To learn more about PWS click here.
- Cutaneous capillary malformations which are reticulated, widespread on body ranging from few to hundreds of oval/circular macules or patches varying in size from few mm to several cm. These anomalies are found in two syndromes:
CM of MIC-CAP (microcephaly-capillary malformation)
CM of MCAP (megalencephaly-capillary malformation-polymicrogyria)
- CM of MIC-CAP (microcephaly-capillary malformation)
- CM of MCAP (megalencephaly-capillary malformation-polymicrogyria)
- Usually multiple, these malformations can be round to oval, can vary from pink-red to tan,and are found in patches of 1 to 2 cm in size. These patches are scattered throughout the body and new ones may continue to appear throughout childhood. Sometimes a high flow murmur can be heard using Doppler device.
- These are found in Capillary malformation-arteriovenous malformation syndrome, an autosomal dominant syndrome associated with mutations in RASA1.
- A congenital, vascular malformation consisting of capillary and venous sized vessels. Presentation is similar to physiologic cutis marmorata with a fixed reticulate erythema but unlike physiologic cutis marmorata, the erythema does not resolve with warming and may be associated with skin ulceration, atrophy of the skin, and undergrowth of the involved extremity.  
- Findings may include prominent veins, telangiectasias, cutaneous atrophy, ulceration, and hyperkeratosis. May have localized or generalized appearance. In localized pattern, the lesions are confined to one side of the body, not crossing midline with or without sharp demarcation. 
- May be associated with a number of other abnormalities, of which limb asymmetry is the most common. Others may include glaucoma, port wine stains, angiokeratomas, hemangiomas. It may also be associated with Sturge-Weber syndrome. Most cases tend be sporadic but autosomal recessive pattern has been observed in familial cases.
- Diagnosis is clinical and depends on history and examination. Management depends on the systemic involvement. Skin lesions tend to improve spontaneously.
- "Permanent dilation of preexisting blood vessels creating small focal red lesions, most commonly in the skin or mucous membranes. It is characterized by the prominence of skin blood vessels, such as vascular spiders." To learn about Hereditary hemorrhagic telangiectasia (HHT) click here.

### Lymphatic malformations (LM)
- benign lesions consisting of dilated lymphatic channels or cysts lined by cells of endothelial origin with lymphatic differentiation. If these lesions are associated with overgrowth then some of these lesions belong to the PIK3CA-related overgrowth spectrum. 
- These are classified as follows:
Macrocystic  LM
Microcystic  LM
Mixed cystic LM
Macrocystic  LM
Also called cystic hygroma, and cystic lymphangioma. A cystic growth consisting of large, interconnected lymphatic cysts lined by a thin endothelium. Usually found in neck, axilla and groin. Presents as a large, poorly delineated, translucent, soft cystic mass covered by normal skin.
May be associated with chromosomal abnormalities such as Down syndrome, Turner syndrome. To learn more click here.
Microcystic  LM
Also known as 'lymphangioma circumscriptum', these lymphatic anomalies may be present at birth or may develop in first few years of life. Usual presentation is as a cluster of clear, translucent or hemorrhagic vesicles that may cause pressure symptoms as they grow in size.
Usually affect deep seated structures and frequent locations are proximal extremities, trunk, axilla, and the oral cavity.
Diagnosis is clinical and treatment options include surgery, sclerotherapy, radiotherapy, and laser therapy. Recently topical sirolimus has also been used. To learn more click here.
- Macrocystic  LM
- Microcystic  LM
- Mixed cystic LM
- Macrocystic  LM
Also called cystic hygroma, and cystic lymphangioma. A cystic growth consisting of large, interconnected lymphatic cysts lined by a thin endothelium. Usually found in neck, axilla and groin. Presents as a large, poorly delineated, translucent, soft cystic mass covered by normal skin.
May be associated with chromosomal abnormalities such as Down syndrome, Turner syndrome. To learn more click here.
- Also called cystic hygroma, and cystic lymphangioma. A cystic growth consisting of large, interconnected lymphatic cysts lined by a thin endothelium. Usually found in neck, axilla and groin. Presents as a large, poorly delineated, translucent, soft cystic mass covered by normal skin.
- May be associated with chromosomal abnormalities such as Down syndrome, Turner syndrome. To learn more click here.
- Microcystic  LM
Also known as 'lymphangioma circumscriptum', these lymphatic anomalies may be present at birth or may develop in first few years of life. Usual presentation is as a cluster of clear, translucent or hemorrhagic vesicles that may cause pressure symptoms as they grow in size.
Usually affect deep seated structures and frequent locations are proximal extremities, trunk, axilla, and the oral cavity.
Diagnosis is clinical and treatment options include surgery, sclerotherapy, radiotherapy, and laser therapy. Recently topical sirolimus has also been used. To learn more click here.
- Also known as 'lymphangioma circumscriptum', these lymphatic anomalies may be present at birth or may develop in first few years of life. Usual presentation is as a cluster of clear, translucent or hemorrhagic vesicles that may cause pressure symptoms as they grow in size.
- Usually affect deep seated structures and frequent locations are proximal extremities, trunk, axilla, and the oral cavity.
- Diagnosis is clinical and treatment options include surgery, sclerotherapy, radiotherapy, and laser therapy. Recently topical sirolimus has also been used. To learn more click here.
- Diffuse or multicentric proliferation of dilated lymphatic vessels that may involve skin, bones, and internal organs. The proliferating vessels resemble common lymphatic malformations but the disease involvement is multi-system. Lungs, bones and mediastinum are most commonly affected but skin, liver and spleen are commonly affected as well. Liver, spleen, and thoracic duct involvement typically indicates worse prognosis.
- Considered to b sporadic and non-hereditary, it may present in childhood or can be diagnosed later in life. Etiology is unknown but high levels of VEGFR-3 have been reported in patient population.
- Chylothorax due to leakage of lymphtic fluid is commonly encountered and is difficult to treat. Patient may present with respiratory symptoms such as chest pain, wheezing, SOB, cough, repeated infections or symptoms due to involvement of other organs such as bone pain, pathological fractures, pelvic or abdominal pain, swelling, fever, internal bleeding, skin lesions.
- Diagnosis of GLA is very challenging and requires multidisciplinary input. It depends on history, examination, imaging studies such as MRI, contrast ultrasound, magnetic resonance lymphangiogram, CXR,near-infrared fluorescence lymphatic imaging, nanotechnology-based MRI agents and biopsy. Sometimes surgery is required that can be both diagnostic and therapeutic.
- Management is usually focused on symptomatic improvement. Options include chest drainage, open thorax surgery, sclerotherapy, surgical removal (debulking), lymphatic anastomosis and medical therapies such as sirolimus and interferon.
Kaposiform lymphangiomatosis (KLA)
A rare subtype with worse pronosis. Malformed vessels occur with cluster and sheets of spindle lymphatic endothelial cells. Consumptive coagulopathy is also a feature.
Intra-thoracic component is often the cause of mortality. Currently there are no treatment guidelines.
- Kaposiform lymphangiomatosis (KLA)
A rare subtype with worse pronosis. Malformed vessels occur with cluster and sheets of spindle lymphatic endothelial cells. Consumptive coagulopathy is also a feature.
Intra-thoracic component is often the cause of mortality. Currently there are no treatment guidelines.
- A rare subtype with worse pronosis. Malformed vessels occur with cluster and sheets of spindle lymphatic endothelial cells. Consumptive coagulopathy is also a feature.
- Intra-thoracic component is often the cause of mortality. Currently there are no treatment guidelines.
- Lymphatic malformation in Gorham-Stout disease affect a single or multiple bones and adjacent soft tissues, leading to progressive osteolysis and invasion of the bone cortex. Was originally described as disappearing or vanishing bone disease. GSD progression often leads to visceral, abdominal and thoracic involvement that may cause effusion and ascites The osteolysis is progressive in GSD as compared to non-progressive osteolysis in GLA.
- There are two distinct forms of GSD. Primary form involves multiple bones and tissues with multi-focal lesions as described above versus trauma induced GSD that typically involves one or closely adjacent one and is usually self limited.
- The etiology has not been established and gender, genetic inheritance, or race seem to play no role but inflammation, trauma and puberty have been thought to pay a role. Activation of platelet derived growth factor pathway and up regulation of lymphangiogenesis stimulating pathways may play a role in pathogenesis. IL-6 has been found to be elevated in some patients.
- Symptoms depend on the bone involved and extent of involvement. Patient can experience chest pain, dyspnea, tachypnea, wheezing, SOB, dull ache, back pain, paralysis, loose teeth and facial deformation. The involvement of thorax and development of chylothorax indicate poor prognosis.
- Diagnosis often requires clinical, radiological and histopathological evidence. Imaging studies including MRI and CT scan are often crucial. Management is often symptomatic and encompasses anti-osteoclastic medication and radiotherapy. If disease affects neuro-vascular structures then surgery is indicated.
- Also called  acquired progressive lymphangioma, this vascular anomaly usually presents as asymptomatic, slow growing, reddish brown or violaceous papule, plaque, macule or erythema. Histological studies show numerous, dilated, thin-walled vessels that are lined by flat endothelial cells and are proliferating. No nuclear atypia has been demonstrated in this locally aggressive tumor. The cells appear to dissect between the collagen fibers.
- Excision is usually the treatment of choice but some other therapies such as Imiquimod 5% cream have been tried.
- Edema due to obstruction or disorder of lymphatic vessels and lymph nodes. Can present at any stage of life but majority of he cases present at puberty.
- Treatment is usually conservative by compression therapy that may include complex physical therapy, pneumatic pumps and compressive garments. Some cases may require volume reducing surgery. Lymphatic microsurgery is being tried in some experimental studies.
Nonne-Milroy syndrome
A hereditary disorder that usually presents as bilateral edema of lower limbs that may involve the whole extremity or may be limited to legs, feet or toes. This may or may not be accompanied by toenail changes such as upslanting toenails and deep creases in the toes, papillomatosis, hydrocele, hydrothorax, lung hypoplasia and prominent leg veins. A case of unilateral phenotype have also been reported. Swellings may be complicated by recurrent episodes of cellulitis.
The disease typically follows autosomal-dominant pattern though cases of autosomal-recessive inheritance and variable expression has also been reported. The defect thought to be responsible has been located on VEGFR3 (FLT4) gene that codes for vascular endothelial growth factor receptor 3 (VEGFR3).
Primary hereditary lymphedema
Chronic edema that can appear in any body part due to blockage or malfunctioning of lymphatic channels that may lead to recurrent infections and impairment.
Results from mutations in VEGFC gene that encodes the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4). This gene plays an important role in lymphangiogenesis.
Primary hereditary lymphedema
Edema typically first appears in legs and then progresses to involve the arms.
Thought to be associated with muatation in GJC2 gene that encodes for connexin-47, a member of the gap junction connecxin family. Mutation in this gene has also been linked to Pelizaeus-Merzbacher-like disease type 1 and spastic paraplegia type 44.
Lymphedema-distichiasis
A syndrome that is characterized by edema that typically manifests in lower limb and distichiasis that is an anomaly of eyelashes. Distichiasis appears earlier in life than lymphedema and manifests as extra eyelashes that typically arise from meibomian glands. This syndrome has been associated with congenital heart disease, varicose veins, cleft palate, ptosis, strabismus, renal abnormalities, spinal extradural cysts, and neck webbing.
Inherited in autosomal dominant pattern mutation in FOXC2 gene that encodes for transcription factors. Inheritance also shows variable expression.
Diagnosis is clinical. Treatment for lymphedema is mainly conservative with management of complications such as cellulitis. Treatment for distichiasis consists of symptomatic management such as lubrication or definitive management such as surgery, cryotherapy, or electrolysis.
Hypotrichosis-lymphedema-telangiectasia
Characterized by less than normal body hair (hypotrichosis), chronic swelling of the body (lymphedema), and dilated blood vessels (telangiectasia). These usually appear at birth or early in life and then progressively worsen over time. Hypotrichosis may present as absent eyebrows, eyelashes and alopecia or may manifest as sparse body hair. Lymphedema typically has predilection for lower limbs and telangiectasia are more commonly seen on palms although plantar telangiectasia are also seen. This syndrome has also been associated with cutis marmorata, hydrocele, palpebral edema, ascites, dermal atrophy, small cutaneous papular vascular lesions, skin degeneration, hydrops fetalis, pleural effusion, renal defects, aortic dilation and abnormal nails.
Mutation in SOX18 gene that encodes for transcription factor SOX18 is thought to be the cause of this syndrome. This transcription factor is expressed widely in body tissues and that may explain the wide ranging manifestations of this syndrome. Inheritance can both be autosomal-dominant and autosomal-recessive.
There is no definitive treatment for this syndrome. Management is based on genetic counseling and symptomatic treatment.
Primary lymphedema with myelodysplasia
Also called Emberger syndrome, this anomaly presents with wide variety of phenotypes including congenital sensorineural deafness, lymphedema, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), hypotelorism, epicanthic folds, long tapering fingers and/or neck webbing, and generalized warts.. Lymphedema has predisposition for lower limbs. Patient may present with complication of these phenotypes such as infections, bleeding and recurrent cellulitis.
Deficiency of transcription factor GATA2 due to mutations in GATA2 gene is thought to play the critical role. Inheritance tends to follow autosomal-dominant pattern.
Screening for GATA2 muations is indicated in patients who present with lymphedema and hematological abnormalities. Children should be screened for hematological disorders if they present with lower limb lymphedema. Besides symptomatic treatment for lymphedema and standard treatment for deafness, primary stem cell transplant is indicated for hematological malignancies. 
Primary generalized lymphatic anomaly
Also called Hennekam lymphangiectasia-lymphedema syndrome, this disorder is characterized by generalized lymphatic anomalies such as lymphangiectasia and lymphedema, typical dysmorphic features such as flat nasal bridge, hypertelorism, small mouth and variable intellectual disability that may present as developmental delay. Lymphangiectasias are typically found in intestines and can cause generalized body swelling due to loss of proteins but can also be found in other organs such as kidney, thyroid gland and pleura.
Mutations in CCBE1 gene are thought to be the main culprit although mutations in FAT4 gene has also be linked by some studies. CCBE1 encodes for Collagen- and calcium-binding EGF domain-containing protein 1 (CCBE1) that plays a crucial role in activation of vascular endothelial growth factor-C (VEGFC) through its collagen domain. Inheritance tends to follow autosomal-recessive pattern.
Diagnosis depends on history and examination, lab findings, and genetic testing for associated mutations. Analysis for CCBE1 mutation should be considered in patients presenting with unexplained lymphatic anomalies, and/or unexplained intellectual disability. No definitive management is available at this point. Conservative measures for lymphedema and protein deficiency, and rehabilitation for intellectual disability is the mainstay of management.
Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome
As name indicates, this syndrome is characterized by microcephaly that is often accompanied by intellectual disability, congenital lymphedema and ocular findings. Ocular defects, often because of chorioretinal dysplasia, may include peripheral retinal pigmentation, retinal folds, chorioretinopathy, widespread chorioretinal atrophy, hyperopia, small corneas, nystagmus and small optic nerves. Microcephaly can be variable and imaging often shows small size brain. Intellectual disability can also vary from normal developmental to severe mental retardation. Lymphedema most often involves lower limbs and may or may not resolve spontaneously. Facial features are distinct with broad nose, anteverted nares, upslanting palpebral fissures, a rounded nasal tip, a long philtrum, a pointed chin, a thin upper lip, prominent ears, and patient may also have atrial septal defects.
Mutations in KIF11 gene that encodes for spindle motor protein of kinesin family, a protein that plays a role in mitosis, are thought to cause this syndrome. These mutations can be sporadic or hereditary, and when hereditary they follow autosomal-dominant pattern with variable expression and reduced penetrance.
Diagnosis requires genetic testing in addition to clinical findings. Long term cardiac and ophthalmologic follow-ups are recommended.
Lymphedema-choanal atresia
A very rare syndrome described in 1982 in a Middle Eastern family when individuals in the family presented with bilateral posterior choanal atresia with other developmental abnormalities such as high arched palate, hypoplastic nipples, pericardial effusion, and pectus excavatum. Follow up detected lymphedema in five individuals with choanal atresia in the family later in 1991.
Deletion in PTPN14 gene that appeared to follow autosomal-recessive pattern are thought to be the cause. This gene encodes for a protein that is thought to be involved in cell-signaling pathways and regulation of cellular functions.
- Nonne-Milroy syndrome
A hereditary disorder that usually presents as bilateral edema of lower limbs that may involve the whole extremity or may be limited to legs, feet or toes. This may or may not be accompanied by toenail changes such as upslanting toenails and deep creases in the toes, papillomatosis, hydrocele, hydrothorax, lung hypoplasia and prominent leg veins. A case of unilateral phenotype have also been reported. Swellings may be complicated by recurrent episodes of cellulitis.
The disease typically follows autosomal-dominant pattern though cases of autosomal-recessive inheritance and variable expression has also been reported. The defect thought to be responsible has been located on VEGFR3 (FLT4) gene that codes for vascular endothelial growth factor receptor 3 (VEGFR3).
- A hereditary disorder that usually presents as bilateral edema of lower limbs that may involve the whole extremity or may be limited to legs, feet or toes. This may or may not be accompanied by toenail changes such as upslanting toenails and deep creases in the toes, papillomatosis, hydrocele, hydrothorax, lung hypoplasia and prominent leg veins. A case of unilateral phenotype have also been reported. Swellings may be complicated by recurrent episodes of cellulitis.
- The disease typically follows autosomal-dominant pattern though cases of autosomal-recessive inheritance and variable expression has also been reported. The defect thought to be responsible has been located on VEGFR3 (FLT4) gene that codes for vascular endothelial growth factor receptor 3 (VEGFR3).
- Primary hereditary lymphedema
Chronic edema that can appear in any body part due to blockage or malfunctioning of lymphatic channels that may lead to recurrent infections and impairment.
Results from mutations in VEGFC gene that encodes the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4). This gene plays an important role in lymphangiogenesis.
- Chronic edema that can appear in any body part due to blockage or malfunctioning of lymphatic channels that may lead to recurrent infections and impairment.
- Results from mutations in VEGFC gene that encodes the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4). This gene plays an important role in lymphangiogenesis.
- Primary hereditary lymphedema
Edema typically first appears in legs and then progresses to involve the arms.
Thought to be associated with muatation in GJC2 gene that encodes for connexin-47, a member of the gap junction connecxin family. Mutation in this gene has also been linked to Pelizaeus-Merzbacher-like disease type 1 and spastic paraplegia type 44.
- Edema typically first appears in legs and then progresses to involve the arms.
- Thought to be associated with muatation in GJC2 gene that encodes for connexin-47, a member of the gap junction connecxin family. Mutation in this gene has also been linked to Pelizaeus-Merzbacher-like disease type 1 and spastic paraplegia type 44.
- Lymphedema-distichiasis
A syndrome that is characterized by edema that typically manifests in lower limb and distichiasis that is an anomaly of eyelashes. Distichiasis appears earlier in life than lymphedema and manifests as extra eyelashes that typically arise from meibomian glands. This syndrome has been associated with congenital heart disease, varicose veins, cleft palate, ptosis, strabismus, renal abnormalities, spinal extradural cysts, and neck webbing.
Inherited in autosomal dominant pattern mutation in FOXC2 gene that encodes for transcription factors. Inheritance also shows variable expression.
Diagnosis is clinical. Treatment for lymphedema is mainly conservative with management of complications such as cellulitis. Treatment for distichiasis consists of symptomatic management such as lubrication or definitive management such as surgery, cryotherapy, or electrolysis.
- A syndrome that is characterized by edema that typically manifests in lower limb and distichiasis that is an anomaly of eyelashes. Distichiasis appears earlier in life than lymphedema and manifests as extra eyelashes that typically arise from meibomian glands. This syndrome has been associated with congenital heart disease, varicose veins, cleft palate, ptosis, strabismus, renal abnormalities, spinal extradural cysts, and neck webbing.
- Inherited in autosomal dominant pattern mutation in FOXC2 gene that encodes for transcription factors. Inheritance also shows variable expression.
- Diagnosis is clinical. Treatment for lymphedema is mainly conservative with management of complications such as cellulitis. Treatment for distichiasis consists of symptomatic management such as lubrication or definitive management such as surgery, cryotherapy, or electrolysis.
- Hypotrichosis-lymphedema-telangiectasia
Characterized by less than normal body hair (hypotrichosis), chronic swelling of the body (lymphedema), and dilated blood vessels (telangiectasia). These usually appear at birth or early in life and then progressively worsen over time. Hypotrichosis may present as absent eyebrows, eyelashes and alopecia or may manifest as sparse body hair. Lymphedema typically has predilection for lower limbs and telangiectasia are more commonly seen on palms although plantar telangiectasia are also seen. This syndrome has also been associated with cutis marmorata, hydrocele, palpebral edema, ascites, dermal atrophy, small cutaneous papular vascular lesions, skin degeneration, hydrops fetalis, pleural effusion, renal defects, aortic dilation and abnormal nails.
Mutation in SOX18 gene that encodes for transcription factor SOX18 is thought to be the cause of this syndrome. This transcription factor is expressed widely in body tissues and that may explain the wide ranging manifestations of this syndrome. Inheritance can both be autosomal-dominant and autosomal-recessive.
There is no definitive treatment for this syndrome. Management is based on genetic counseling and symptomatic treatment.
- Characterized by less than normal body hair (hypotrichosis), chronic swelling of the body (lymphedema), and dilated blood vessels (telangiectasia). These usually appear at birth or early in life and then progressively worsen over time. Hypotrichosis may present as absent eyebrows, eyelashes and alopecia or may manifest as sparse body hair. Lymphedema typically has predilection for lower limbs and telangiectasia are more commonly seen on palms although plantar telangiectasia are also seen. This syndrome has also been associated with cutis marmorata, hydrocele, palpebral edema, ascites, dermal atrophy, small cutaneous papular vascular lesions, skin degeneration, hydrops fetalis, pleural effusion, renal defects, aortic dilation and abnormal nails.
- Mutation in SOX18 gene that encodes for transcription factor SOX18 is thought to be the cause of this syndrome. This transcription factor is expressed widely in body tissues and that may explain the wide ranging manifestations of this syndrome. Inheritance can both be autosomal-dominant and autosomal-recessive.
- There is no definitive treatment for this syndrome. Management is based on genetic counseling and symptomatic treatment.
- Primary lymphedema with myelodysplasia
Also called Emberger syndrome, this anomaly presents with wide variety of phenotypes including congenital sensorineural deafness, lymphedema, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), hypotelorism, epicanthic folds, long tapering fingers and/or neck webbing, and generalized warts.. Lymphedema has predisposition for lower limbs. Patient may present with complication of these phenotypes such as infections, bleeding and recurrent cellulitis.
Deficiency of transcription factor GATA2 due to mutations in GATA2 gene is thought to play the critical role. Inheritance tends to follow autosomal-dominant pattern.
Screening for GATA2 muations is indicated in patients who present with lymphedema and hematological abnormalities. Children should be screened for hematological disorders if they present with lower limb lymphedema. Besides symptomatic treatment for lymphedema and standard treatment for deafness, primary stem cell transplant is indicated for hematological malignancies. 
- Also called Emberger syndrome, this anomaly presents with wide variety of phenotypes including congenital sensorineural deafness, lymphedema, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), hypotelorism, epicanthic folds, long tapering fingers and/or neck webbing, and generalized warts.. Lymphedema has predisposition for lower limbs. Patient may present with complication of these phenotypes such as infections, bleeding and recurrent cellulitis.
- Deficiency of transcription factor GATA2 due to mutations in GATA2 gene is thought to play the critical role. Inheritance tends to follow autosomal-dominant pattern.
- Screening for GATA2 muations is indicated in patients who present with lymphedema and hematological abnormalities. Children should be screened for hematological disorders if they present with lower limb lymphedema. Besides symptomatic treatment for lymphedema and standard treatment for deafness, primary stem cell transplant is indicated for hematological malignancies. 
- Primary generalized lymphatic anomaly
Also called Hennekam lymphangiectasia-lymphedema syndrome, this disorder is characterized by generalized lymphatic anomalies such as lymphangiectasia and lymphedema, typical dysmorphic features such as flat nasal bridge, hypertelorism, small mouth and variable intellectual disability that may present as developmental delay. Lymphangiectasias are typically found in intestines and can cause generalized body swelling due to loss of proteins but can also be found in other organs such as kidney, thyroid gland and pleura.
Mutations in CCBE1 gene are thought to be the main culprit although mutations in FAT4 gene has also be linked by some studies. CCBE1 encodes for Collagen- and calcium-binding EGF domain-containing protein 1 (CCBE1) that plays a crucial role in activation of vascular endothelial growth factor-C (VEGFC) through its collagen domain. Inheritance tends to follow autosomal-recessive pattern.
Diagnosis depends on history and examination, lab findings, and genetic testing for associated mutations. Analysis for CCBE1 mutation should be considered in patients presenting with unexplained lymphatic anomalies, and/or unexplained intellectual disability. No definitive management is available at this point. Conservative measures for lymphedema and protein deficiency, and rehabilitation for intellectual disability is the mainstay of management.
- Also called Hennekam lymphangiectasia-lymphedema syndrome, this disorder is characterized by generalized lymphatic anomalies such as lymphangiectasia and lymphedema, typical dysmorphic features such as flat nasal bridge, hypertelorism, small mouth and variable intellectual disability that may present as developmental delay. Lymphangiectasias are typically found in intestines and can cause generalized body swelling due to loss of proteins but can also be found in other organs such as kidney, thyroid gland and pleura.
- Mutations in CCBE1 gene are thought to be the main culprit although mutations in FAT4 gene has also be linked by some studies. CCBE1 encodes for Collagen- and calcium-binding EGF domain-containing protein 1 (CCBE1) that plays a crucial role in activation of vascular endothelial growth factor-C (VEGFC) through its collagen domain. Inheritance tends to follow autosomal-recessive pattern.
- Diagnosis depends on history and examination, lab findings, and genetic testing for associated mutations. Analysis for CCBE1 mutation should be considered in patients presenting with unexplained lymphatic anomalies, and/or unexplained intellectual disability. No definitive management is available at this point. Conservative measures for lymphedema and protein deficiency, and rehabilitation for intellectual disability is the mainstay of management.
- Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome
As name indicates, this syndrome is characterized by microcephaly that is often accompanied by intellectual disability, congenital lymphedema and ocular findings. Ocular defects, often because of chorioretinal dysplasia, may include peripheral retinal pigmentation, retinal folds, chorioretinopathy, widespread chorioretinal atrophy, hyperopia, small corneas, nystagmus and small optic nerves. Microcephaly can be variable and imaging often shows small size brain. Intellectual disability can also vary from normal developmental to severe mental retardation. Lymphedema most often involves lower limbs and may or may not resolve spontaneously. Facial features are distinct with broad nose, anteverted nares, upslanting palpebral fissures, a rounded nasal tip, a long philtrum, a pointed chin, a thin upper lip, prominent ears, and patient may also have atrial septal defects.
Mutations in KIF11 gene that encodes for spindle motor protein of kinesin family, a protein that plays a role in mitosis, are thought to cause this syndrome. These mutations can be sporadic or hereditary, and when hereditary they follow autosomal-dominant pattern with variable expression and reduced penetrance.
Diagnosis requires genetic testing in addition to clinical findings. Long term cardiac and ophthalmologic follow-ups are recommended.
- As name indicates, this syndrome is characterized by microcephaly that is often accompanied by intellectual disability, congenital lymphedema and ocular findings. Ocular defects, often because of chorioretinal dysplasia, may include peripheral retinal pigmentation, retinal folds, chorioretinopathy, widespread chorioretinal atrophy, hyperopia, small corneas, nystagmus and small optic nerves. Microcephaly can be variable and imaging often shows small size brain. Intellectual disability can also vary from normal developmental to severe mental retardation. Lymphedema most often involves lower limbs and may or may not resolve spontaneously. Facial features are distinct with broad nose, anteverted nares, upslanting palpebral fissures, a rounded nasal tip, a long philtrum, a pointed chin, a thin upper lip, prominent ears, and patient may also have atrial septal defects.
- Mutations in KIF11 gene that encodes for spindle motor protein of kinesin family, a protein that plays a role in mitosis, are thought to cause this syndrome. These mutations can be sporadic or hereditary, and when hereditary they follow autosomal-dominant pattern with variable expression and reduced penetrance.
- Diagnosis requires genetic testing in addition to clinical findings. Long term cardiac and ophthalmologic follow-ups are recommended.
- Lymphedema-choanal atresia
A very rare syndrome described in 1982 in a Middle Eastern family when individuals in the family presented with bilateral posterior choanal atresia with other developmental abnormalities such as high arched palate, hypoplastic nipples, pericardial effusion, and pectus excavatum. Follow up detected lymphedema in five individuals with choanal atresia in the family later in 1991.
Deletion in PTPN14 gene that appeared to follow autosomal-recessive pattern are thought to be the cause. This gene encodes for a protein that is thought to be involved in cell-signaling pathways and regulation of cellular functions.
- A very rare syndrome described in 1982 in a Middle Eastern family when individuals in the family presented with bilateral posterior choanal atresia with other developmental abnormalities such as high arched palate, hypoplastic nipples, pericardial effusion, and pectus excavatum. Follow up detected lymphedema in five individuals with choanal atresia in the family later in 1991.
- Deletion in PTPN14 gene that appeared to follow autosomal-recessive pattern are thought to be the cause. This gene encodes for a protein that is thought to be involved in cell-signaling pathways and regulation of cellular functions.

### Venous malformations (VM)
- Localized defects characterized by dilated venous channels. Microscopically they consist of thin endothelial cells lined by fewer, disorganized smooth muscle cells and extracellular matrix. Patient may present with deforming lesions, bleeding, thrombosis, significant acute or chronic pain, and pressure symptoms. Located on skin and mucosa for majority of the times, lesions often are present at birth.
- Sporadic mutations in the TEK gene, that encodes the tyrosine kinase receptor TIE2 that functions to regulate cellular growth and proliferation are found in half of the patients with sporadic venous malformations.
- Diagnosis is clinical. Current treatment options include sclerotherapy and surgery, alone or in combination but inaccessible lesions and high recurrence rate remains a problem. mTOR inhibitor rapamycin has been used in some studies with success.
- Venous malformations that appear both on skin and mucous membranes.  Present at birth, they may not be apparent early in life and can appear after trauma and during pregnancy and puberty because of rapid growth. Patient may present with sequela of these malformations such as cosmetic deformation, pain, bleeding.
- Associated with mutation in TEK/TIE2 receptor tyrosine kinase that plays critical role in development of vessels and cardiovascular system.
- Also called Bean's syndrome and diffuse angiomatosis, venous malformations in this disorder involve the skin, oral cavity and internal organs, most typically the gastrointestinal tract. Cutaneous malformations are bluish in color, generally smaller than 1-2 cm, often hyperkeratotic, compressible and often found at palms and soles. Anomalies on the skin are usually asymptomatic but GI malformations can cause hemorrhage that can lead to anemia, most frequent presentation in patient population. Other manifestation can include GI infarction, telescoping or twisting of GI tract leading to intussusception and volvulus.
- Thought to be caused by somatic double (cis) muatations in TEK gene although autosomal-dominant inheritance has also been described in some cases. The gene that encodes TIE2, receptor tyrosine kinase involved in cell-signaling.
- The documentation of gastrointestinal lesions by endoscopy, colonoscopy, CT scan or MRI is considered pathognomonic. Sclerotherapy and surgery such as enterotomy remain the mainstay of treatment along with symptomatic management such as long term iron supplementation and/or blood transfusions.
- Defined by presence of glomus cells in in smooth muscle layer of the vessels, these mesynchymal vascular anomaly arises from glomus bodies, arteriovenous anastomosis that help regulate temperature via shunting of blood through its unique neuromyoarterial structure. Classically found in digits, they can occur anywhere but widespread lesions are not common. Clinical presentation varies from asymptomatic bluish to reddish plaques and nodules that are often partially compressible and are tender to painful disfiguring lesions.
- Mutations in glomulin (GLMN) gene that leads to defective GLMN protein is thought to be the cause. GMLN protein binds Rbx1 and inhibits its E3 ubiquitin ligase activity. If GMLN is defective then it leads to increased activity of Rbx1 causing decreased levels of Fbw7 and thus increased levels of Cyclin E and c-Myc because Fbw7 facilitates the ubiquitination and degradation Cyclin E and c-Myc.Mutations are inherited in autosomal-dominant pattern with incomplete pattern and variable expression although sporadic cases have been reported.
- Imaging such as MRI and CT scan and ultrasound can localize and define the extent of disease but definitive diagnosis requires biopsy following by histopathological studies demonstrating  proliferation of glomus cells and venous malformations. Current treatment modalities include surgical excision and sclerotherapy although recurrence is common. Recently electron beam radiation and Nd:YAG laser have been used with success.
- Characterized by clusters of malformed endothelial channels forming densely arranged sinusoids that possess little to no intervening brain tissues. Because they lack smooth muscles and connective tissue and are malformed, they are prone to leakage causing micro-hemorrhages and thrombosis leading to hemosiderin deposits and gliosis around them. They can remain asymptomatic throughout life making them incidental finding but can cause symptoms associated with hemorrhage and pressure effects such as  headaches, seizures, stroke, and focal neurologic deficits.
- Mutations in CCM1 Krev interaction trapped protein 1 (KRIT1), CCM2 Malcavernin, and CCM3 Programmed cell death protein 10 (PDCD10) are thought to be the cause of familial cases that tend to be inherited in autosomal-dominant pattern with incomplete penetrance, and variable expression. These proteins interact with cytoskeleton and endothelial tight junctions during vascular development in neural tissues to help maintain endothelial barrier function. they can occur due to sporadic mutations, usually presenting as single cavernous malformation while familial cases typically present as multiple cavernous malformations.
- Magnetic resonance (MR) imaging techniques are diagnostic modality of choice. Current treatment options depend on clinical history and location of the malformations. Surgery is usually preferred for symptomatic lesions in easily accessible locations and by some, for refractory epilepsy. If asymptomatic, observation is recommended but in case of single accessible asymptomatic malformation, surgical resection can be done. Surgery is also not recommended for malformations located in brain-stem due to significant mortality and morbidity associated with surgery while some recommend surgery after a second symptomatic bleed. Guidelines for symptomatic lesions located deep vary. Radiosurgery can be an alternative modality for single, symptomatic lesion if risks associated with surgery are unacceptable.
- Described as enlargement and expansion of malformed blood vessels that is severe and progressive, typically in skull, face, and vertebral column. Another typical finding is mid-line abnormalities such as diastasis recti, supraumbilical raphe, and hiatus hernia. Clinical presentation can vary but increasing intracranial pressure and hemorrhage after any surgical procedure such as extraction of tooth are of major concern. Other common findings include pain, enlarging tissues such as expanding jaw, bluish mass/swelling, loose tooth, spontaneous bleeding, and ulceration.
- Mutations in ELMO2 gene encoding engulfment and cell motility protein 2 (ELMO2) are thought to be the cause of these malformations. This protein s involved cell-signaling cascade through its attachment to cell membrane. Majority of the cases are sporadic but recently some familial cases with autosomal-recessive inheritance have been described.
- CT angiography and magnetic resonance techniques are the preferred diagnostic modalities and may show widening of neurovascular canal on CTA, hyperintense signal on MRI. Honeycomb and sunburst radiographic appearances have been described as well. Management options include embolization, sclerotherapy, and surgical extirpation.
- Formerly verrucous hemangioma, this rare congenital malformation is characterized by dilated blood vessels reaching out from papillary layer of dermis into subcutaneous tissue. Earlier presentation is bluish lesion that develops warty surface later on. Painful enlarging mass is the typical complain in symptomatic patients.
- Somatic mutation in MAP3K3 mitogen-activated protein kinase kinase kinase 3 are thought to be the cause.
- MRI is the diagnostic modality of choice but histopathological confirmation is gold standard for accurate diagnosis because of its close resemblance with angiokeratoma. Superficial ablation, surgical excision are treatment choices. Recently sirolimus has been used in some studies.

# Medical Therapy

# Naural History

# Historical Perspective