Disorder Definitions

Cerebral cavernous malformations (CCM) or angiomas are capillary malformations found in the central nervous system that cause neurological symptoms such as seizures and epilepsy, acute neurological events, and headaches. Patients may become symptomatic at any age with the majority of patients presenting between the second and fifth decades. Estimates of disease prevalence are between 1:200 to 1:800, based on autopsy and brain MRI studies. The two major forms are a) sporadic accounting for up to 80% of cases, and b) familial (FCCM), accounting for at least 20% of cases. Up to 50% of FCCM cases remain asymptomatic or minimally symptomatic throughout life, but there is a large variability of severity in symptomatic cases even within the same family. There are three known genes that cause this disease, but there are a number of familial cases that remain unexplained by currently available genetic tests. Autosomal dominant inheritance is found in all forms. Cutaneous lesions are found in 9%¹ or more, and retinal lesions in 5%² though these are rarely symptomatic.

The first gene to be identified is KRIT1, or CCM1^{3, 4}. Mutations in this gene account for approximately 40-50% of FCCM. A genetic founder mutation in KRIT1 (Q455X) accounts for the largest population of FCCM worldwide (4). It is found in descendants of Hispanic-Americans who settled in northern New Mexico and the southwestern United States, as well as in the northern Mexico states of Chihuahua and Sonora⁵. Thousands of patients with this mutation, also known as the common Hispanic mutation or CCM1-CHM, are affected with this disease today. Approximately 20% of FCCM cases are caused by CCM2 (CCM2), and another 20-40% by mutations in PDCD10 (CCM3)⁶.

Diagnosis of FCCM is made on the basis of patient and family history, neurological and cutaneous examination, and by brain MRI. FCCM is characterized by multiple lesions on brain MRI with increasing numbers of lesions with increasing age⁷. Advances in MRI have improved detection rates of smaller lesions, but individual lesions can also be very large, several centimeters in greatest diameter. Lesions are best identified on MRI using Susceptibility Weighted imaging (SWI)^{8, 9}, or Gradient Echo (GRE) sequences. These techniques may identify hundreds of lesions in a given patient¹⁰. Confirmation of a genetic mutation allows specific genotype identification and has prognostic implications¹¹. Histopathologic confirmation is available for surgical or autopsy specimens. Symptomatic relatives can be diagnosed by DNA for genotype, and brain MRI for lesion identification.

Treatment includes symptomatic treatment of seizures and epilepsy, prophylactic and symptomatic management of headaches, and rehabilitation for acute neurological events. Selective surgical resection of accessible symptomatic lesions is available to prevent recurrent hemorrhage. Pharmacologic agents that increase risk of hemorrhage or increase blood pressure should be avoided when possible. Surveillance for changes in lesions can be accomplished with MRI but may not change management unless lesion-related symptoms are changing.

Histopathology shows closely clustered enlarged capillary channels with a single layer of endothelium with no intervening brain parenchyma, often associated with thrombus and intra- and extralesional hemorrhage^{12, 13}. Ultrastructurally, tight junctions between endothelial cells are disrupted. Pathogenesis has been partially elucidated through the study of zebrafish and murine animal models with demonstration of the role of KRIT1 in antiangiogenesis through inhibition of endothelial proliferation, apoptosis, migration, lumen formation, and sprouting angiogenesis in endothelial cells in humans¹⁸. Gene mutations in all types of FCCM are loss of function mutations. A two-hit hypothesis appears to explain the development of localized lesions through loss of a second allele¹⁴. Three pharmacologic agents have been shown to reduce lesion permeability in murine models including simvastatin¹⁵, fasudil¹⁶ and sorefenib^{17, 18}. The three known genes appear to interact and may involve common signaling pathways¹⁸.

References:

1. Sirvente J, Enjolras O, Wassef M, Tournier-Lasserve E, Labauge P. Frequency and phenotypes of cutaneous vascular malformations in a consecutive series of 417 patients with familial cerebral cavernous malformations. J Eur Acad Dermatol Venereol. Sep 2009;23(9):1066-1072.
2. Labauge P, Krivosic V, Denier C, Tournier-Lasserve E, Gaudric A. Frequency of retinal cavernomas in 60 patients with familial cerebral cavernomas: a clinical and genetic study. Arch Ophthalmol. Jun 2006;124(6):885-886.
3. Laberge-le Couteulx S, Jung HH, Labauge P, et al. Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet. Oct 1999;23(2):189-193.
4. Sahoo T, Johnson EW, Thomas JW, et al. Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum Mol Genet. Nov 1999;8(12):2325-2333.
5. Polymeropoulos MH, Hurko O, Hsu F, et al. Linkage of the locus for cerebral cavernous hemangiomas to human chromosome 7q in four families of Mexican-American descent. Neurology. Mar 1997;48(3):752-757.
6. Liquori CL, Berg MJ, Squitieri F, et al. Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus. Hum Mutat. Jan 2006;27(1):118.
7. Kattapong VJ, Hart BL, Davis LE. Familial cerebral cavernous angiomas: clinical and radiologic studies. Neurology. Mar 1995;45(3 Pt 1):492-497.
8. Cooper AD, Campeau NG, Meissner I. Susceptibility-weighted imaging in familial cerebral cavernous malformations. Neurology. Jul 29 2008;71(5):382.
9. de Souza JM, Domingues RC, Cruz LC, Jr., Domingues FS, Iasbeck T, Gasparetto EL. Susceptibility-weighted imaging for the evaluation of patients with familial cerebral cavernous malformations: a comparison with t2-weighted fast spin-echo and gradient-echo sequences. AJNR Am J Neuroradiol. Jan 2008;29(1):154-158.
10. Petersen TA, Morrison LA, Schrader RM, Hart BL. Familial versus sporadic cavernous malformations: differences in developmental venous anomaly association and lesion phenotype. AJNR Am J Neuroradiol. Feb;31(2):377-382.
11. Denier C, Goutagny S, Labauge P, et al. Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet. Feb 2004;74(2):326-337.
12. Steiger HJ, Markwalder TM, Reulen HJ. Clinicopathological relations of cerebral cavernous angiomas: observations in eleven cases. Neurosurgery. Dec 1987;21(6):879-884.
13. Tu J, Stoodley MA, Morgan MK, Storer KP. Ultrastructural characteristics of hemorrhagic, nonhemorrhagic, and recurrent cavernous malformations. J Neurosurg. Nov 2005;103(5):903-909.
14. Gault J, Shenkar R, Recksiek P, Awad IA. Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion. Stroke. Apr 2005;36(4):872-874.
15. Whitehead KJ, Chan AC, Navankasattusas S, et al. The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat Med. Feb 2009;15(2):177-184.
16. Stockton RA, Shenkar R, Awad IA, Ginsberg MH. Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity. J Exp Med. Apr 12;207(4):881-896.
17. Wustehube J, Bartol A, Liebler SS, et al. Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling. Proc Natl Acad Sci U S A. Jul 13;107(28):12640-12645.
18. Li DY, Whitehead KJ. Evaluating strategies for the treatment of cerebral cavernous malformations. Stroke. Oct;41(10 Suppl):S92-94.
19. Golden MJ, Saeidi S, Liem B, Marchand E, Morrison LA, Hart BL. Sensitivity of patients with familial cerebral cavernous malformations to therapeutic radiation. Medical Imaging and Radiation Oncology, accepted November 11, 2014.

Definition, epidemiology and pathology:

Classically, Sturge-Weber syndrome (SWS) is defined by a facial capillary malformation (port-wine birthmark/ PWB aka port-wine stain) in association with ipsilateral vascular malformations of the eye and/or the brain (Bodensteiner JB, 1999). The brain vascular malformation affects the leptomeninges. Variants exist where only one of these three structures is involved with the vascular malformation (Comi, 2003). SWS is a congenital syndrome that occurs almost exclusively sporadically, and not in families. Precise population-based data does not exist for the prevalence or incidence of SWS. However, port-wine stains occur in 3 per 1,000 live births, and when a capillary malformation involves the forehead to one side and/or the upper eyelid, that individual is at risk for brain and/or eye involvement. The risk ranges between 10-35% depending on the size of the port-wine stain and whether it is unilateral or bilateral (Enjolras et al, 1985; Tallman et al, 1991). Prevalence data obtained from large dermatologic clinics (Enjolras et al, 1985; Tallman et al, 1991) suggests that about 5-10,000 individuals in the United States have SWS.

Port-wine birthmarks consist of ectatic (dilated) capillary-venous blood vessels in the dermis (Rydh et al, 1991). The capillary malformation is flat and pink at birth, lightens after birth, and then later in childhood or in adulthood frequently darkens and begins to thicken. Studies of the extracellular matrix found increased deposition of type IV collagen, laminin and fibronectin around the affected vessels (Mitsuhashi et al, 1988). The vascular malformation of the eye consists of enlarged, tortuous venous vessels that can affect the conjunctiva, episclera, retina and/or choroids. Choroidal thickness can now be monitored in SWS patients with the use of spectral-domain optical coherence tomography in order to discover abnormalities that were previously undetectable (Arora et al, 2013). Glaucoma is the most frequent ophthalmologic complication, affecting about 30-70% of individuals with SWS, and can result in optic atrophy and blindness. The vascular malformation of the brain in SWS consists of enlarged and tortuous leptomeningeal vessels and dilated deep venous vessels, most often involving the occipital cortex.

Impaired venous drainage from the involved brain regions results in reduced arterial perfusion to these regions (Lin et al, 2006). SPECT (Single Photon Emission Computed Tomography) studies in young infants with SWS have shown that cerebral perfusion goes from being generous in the very young infant to being deficient in the involved cortical region by end of the first year (Adamsbaum et al, 1996). The vessels of leptomeningeal angiomas are thin-walled venous structures, many of which are hugely dilated. The vessels are innervated only by noradrenergic sympathetic nerve fibers (Cunha e Sa et al, 1997) and show increased endothelin-1 expression (Rhoten et al, 1997), suggesting that there may be increased vasoconstrictive tone in SWS. The impaired venous drainage through these vessels results in reduced microcirculation and hypoxia in the surrounding brain tissue. Microscopically, the cortical tissue underlying the angioma shows neuronal loss, calcium deposition, hypoplastic blood vessels, breakdown of the blood-brain barrier and gliosis (Comati et al, 2007). Changes are also seen in the underlying white matter: there is an early phase of hypermyelination, which is then followed by white matter loss (Juhasz et al, 2007).

Clinical studies have shown that the vascular malformation of the skin and eye progress at variable rates, with increased dilation and tortuosity of the vessels over time. However, many questions remain regarding the relationship between the port-wine birthmark, the eye involvement, and the neurologic involvement of SWS. The vascular malformation of the brain in SWS consists of enlarged and tortuous, leptomeningeal, vessels, and dilated deep venous vessels. Impaired venous draining from the involved brain regions results in reduced arterial perfusion to these regions (Lin, Barker, Kraut, & Comi, 2003). Susceptibility-weighted imaging and post-contrast T1-weighted MRI scans in children with SWS have demonstrated that some individuals will develop deep draining vessels and venous angiomas over time.

The brain lesions in SWS are progressive, suggesting that there is ongoing angiogenesis in these lesions. Consistent with this idea, increased levels of endothelial proliferation and apoptosis were seen in leptomeningeal vessels from SWS patients relative to those of controls (Comati et al, 2007), as well as overexpression of fibronectin (Comi et al, 2005). The vessels also showed increased levels of expression of VEGF, VEGF receptors 1 and 2, neuropilin, Tie-2, and HIF-1α and HIF-2α (Comati et al, 2007). Thus, leptomeningeal vascular malformations in SWS appear not to be static lesions, but rather show evidence of ongoing vascular remodeling. Our preliminary findings of elevated levels of matrix metalloproteinases in the urine of SWS patients are also consistent with this hypothesis. A new project within the BVMC will be investigating the extent to which this remodeling contributes to the neurologic deterioration versus providing a compensatory mechanism to maintain blood flow.

Clinical context of SWS treatment:

Most affected infants present with focal or complex partial/secondarily generalized seizures in the first year or two of life (Kramer et al, 2000). Other common presentations in infants include early-handedness and the development of a gaze preference (evidence of a visual-field cut). Stroke-like episodes and migraines are also common (Dora and Balkan, 2001; Klapper, 1994). Migraines can lead to stroke-like episodes and seizures, and seizures can lead to migraines and stroke-like episodes. When episodes of seizures and/or stroke-like episodes are recurrent, the child frequently develops a permanent hemiparesis (weakness on one side of the body) and developmental delay. On the other hand, neurologic impairments including hemiparesis, visual field deficits and cognitive impairments can improve if the patient is seizure-free and clinically stable for a prolonged period (Lee et al, 2001). Severity of neurologic progression varies greatly, with some patients demonstrating stable and mild neurologic impairment but others having severe uncontrolled seizures, repeated strokes and loss of vision, strength and cognitive function.

The only factors known to predict severity of neurologic progression and involvement are unilateral versus bilateral (worse) brain involvement and the age of seizure onset (Kramer et al, 2000). Infants presenting with seizures onset at 6 months of age or younger have been found to have greater hemiparesis than those presenting at older ages, and are more likely to have clusters of seizures followed by prolonged seizure-free periods (Kossoff et al, 2009). Whatever the age of seizure onset time, EEGs have been found to progress in most patients from relatively normal to abnormal, involving more epileptiform activity over time (Kossoff et al, 2014), so it is possible that younger onset is related to further progression at a younger age. These studies suggested, however, that neither early onset, nor clustering (Kossoff et al, 2009), nor more advanced EEG progression (Kossoff et al, 2014) were related to an increase in seizure frequency. At older ages, some patients with SWS begin to present with psychiatric and behavioral issues, including learning and attention issues, problems with sleep and mood, as well as substance abuse (Turin et al, 2010). The clinical variability in presentation, severity and progression inherent in SWS, in addition to its rarity, has slowed efforts to identify effective biomarkers, to develop clinical tools and treatment guidelines, and to carry out high quality clinical/translational research.

Some important clinical questions about SWS have been addressed only with case series and limited cohorts due to the rarity of the disease, and so controversies and further questions remain. There is data that suggests low-dose aspirin can control seizures and decrease stroke-like episodes; leading to stabilization or even improvement in clinical outcomes with relatively few side effects. However, clinicians are still conflicted about aspirin’s use and more research is needed (Lance et al, 2013). A higher prevalence of central hypothyroidism has been noted in SWS patients than in the general population, but the small number of subjects available for this single-center study prevents a more precise accounting of overall prevalence in SWS at this time (Comi et al, 2008). Many questions remain completely unanswered. For example, how does a family history of stroke, migraine, endocrine, vascular, or immune disorders impact the clinical manifestations of the individual affected by SWS? What pregnancy exposures or factors occur with increased frequency in individuals with SWS? Which patients would be best served by a hemispherectomy? What is the cognitive outcome after hemispherectomy versus medical management of seizures in SWS? The answers to these and other questions will eventually be addressed with the aid of the consortium database, which allows for the creation of larger cohorts.

One study has explored the use of stimulants in the treatment of attentional difficulties in Sturge-Weber syndrome (Lance, Lanier, Zabel, & Comi, 2014). All 12 of the study patients had SWS brain involvement and suffered from seizures. Most of the SWS patients had comorbid diagnoses, such as, epilepsy (n=12), hemiparesis (n=8), vision deficits (n=6), and headaches (n=8). Eight out of twelve patients reported appetite suppression and/or headaches as side effects. The majority reported benefits and seven patients remained on the stimulant medication at the time of the retrospective review.

Given the clinical variability inherent in SWS, another important goal is the development of safe, minimally invasive, biomarkers and tools to monitor clinical status. Urine vascular biomarkers are a promising area of new investigation. Pioneered by Dr. Moses’ group, urine profiling of vascular biomarkers has previously been used successfully to profile different vascular disorders (infantile hemangioma, other vascular neoplasms, lymphatic malformation and capillary-lymphaticovenous malformations, and extensive and unremitting capillary malformation and arteriovenous malformation) and to separate progressive vascular lesions from stable lesions (Marler et al, 2005), thus providing proof-of-principle that this approach can be used to non-invasively differentiate vascular disorders, sub-group patients, and provide predictive information. A similar approach has proven successful using urine biomarkers to predict breast cancer risk (Pories et al, 2008). Published work with brain tumors also demonstrates that urinary biomarkers can be used to predict response to treatment (Smith et al, 2008). More recently, Dr. Moses's and Dr. Comi's groups examined urinary biomarkers in individuals with and without SWS. They found that the matrix metalloproteinases MMP-2 and MMP-9 are present much more often in the urine of those with SWS than in those without it, and higher levels of these biomarkers have been correlated with poorer clinical status at the time of biomarker measurement. (Sreenivasan et al, 2013). Research into the potential of these biomarkers to predict and measure long-term outcomes is part of ongoing research through the BVMC.

Etiology and pathogenesis of SWS:

SWS occurs almost entirely sporadically and with equal frequency in the sexes (Comi, 2003). The localized abnormalities of blood vessel development and function affecting the facial skin, eye and brain suggest a developmental disruption occurring in the first trimester of pregnancy. Since the abnormal blood vessels in SWS are usually localized to a single region on one side of the body, a somatic mutation (somatic mosaicism) model for the etiology of SWS has been proposed (Happle, 1987). During the first trimester of fetal development the primitive vascular plexus invades the adjacent developing brain, skin, and eye in this region and a somatic mutation could prevent the normal maturation of these vessels. Recently, whole Genome Sequencing of DNA samples from affected and unaffected skin or brain samples of individuals with SWS have been carried out. From these analyses, and subsequent studies, it was determined that SWS is caused by an activating somatic mutation in GNAQ, which likely occurs early in fetal development (Shirley et al, 2013).

The somatic mutation in GNAQ is hyper-activating and impacts the function of GPCRs known to be critical to angiogenesis, vascular function, and vascular remodeling. Gαq (encoded by the GNAQ gene) is a G protein subunit that modulates a wide spectrum of downstream signaling pathways, depending on the biochemical and cellular context (Kimple, Bosch, Giguere, & Siderovski, 2011). In a recent study, the phosphorylation status of several downstream effectors of Gαq after transfection of the R183Q mutation and controls were accessed (Shirley et al, 2013). The R183Q mutants demonstrated moderate constitutive hyper-phosphorylation of ERK and a trend for a similar increase in phosphorylation of JNK. Gαq is associated with GPCRs such as endothelin 1, angiotensin, and serotonin that can all impact vascular development, remodeling, and function (Kimple, Bosch, Giguere, & Siderovski, 2011). The discovery of the precise somatic mosaic mutation causing SWS has catapulted research to investigate the downstream protein signaling pathways involved in the molecular etiology of SWS.

References

1. Adamsbaum C, Pinton F, Rolland Y, Chiron C, Dulac O, Kalifa G. Accelerated myelination in early Sturge-Weber syndrome: MRI-SPECT correlations. Pediatr Radiol. 1996 26, 759-762.
2. Arora KS, Quigley HA, Comi AM, Miller RB, Jampel HD. Increased choroidal thickness in patients with Sturge-Weber syndrome. JAMA Ophthalmol. 2013 131, 1216-1219.
3. Bodensteiner JB RE. Sturge Weber Syndrome (Mt. Freedom, NJ, Sturge Weber Foundation). 1999.
4. Comati A, Beck H, Halliday W, Snipes GJ, Plate KH, Acker T. Upregulation of hypoxia inducible factor (HIF)-1alpha and HIF-2alpha in leptomeningeal vascular malformations of Sturge-Weber syndrome. J Neuropathol Exp Neurol. 2007 66, 86-97.
5. Comi AM. Pathophysiology of Sturge-Weber syndrome. J Child Neurol. 2003 18, 509-516.
6. Comi AM, Bellamkonda S, Ferenc LM, Cohen BA, Germain-Lee EL. Central hypothyroidism and Sturge-Weber syndrome. Pediatr Neurol. 2008 39, 58-62.
7. Comi AM, Weisz CJ, Highet BH, Skolasky RL, Pardo CA, Hess EJ. Sturge-Weber syndrome: altered blood vessel fibronectin expression and morphology. J Child Neurol. 2005 Jul;20(7):572-7.
8. Altered blood vessel fibronectin expression and morphology. J Child Neurol. 2005 20, 572-7.
9. Cunha e Sa M, Barroso CP, Caldas MC, Edvinsson L, Gulbenkian S. Innervation pattern of malformative cortical vessels in Sturge-Weber disease: an histochemical, immunohistochemical, and ultrastructural study. Neurosurgery. 1997 41, 872-876; discussion 876-877.
10. Dora B, Balkan S. Sporadic hemiplegic migraine and Sturge-Weber syndrome. Headache. 2001 41,209-210.
11. Enjolras O, Riche MC, Merland JJ. Facial port-wine stains and Sturge-Weber syndrome. Pediatrics. 1985 76, 48-51.
12. Happle R. Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J Am Acad Dermatol. 1987 16, 899-906.
13. Juhasz C, Lai C, Behen ME, Muzik O, Helder EJ, Chugani DC, Chugani HT. White matter volume as a major predictor of cognitive function in Sturge-Weber syndrome. Arch Neurol. 2007 64, 1169-1174.
14. Kimple AJ, Bosch DE, Giguere PM, Siderovski DP. Regulators of G-protein signaling and their Galpha substrates: promises and challengers in their use as drug discovery targets. Pharmacological Reviews. 2011 63(3), 728-749.
15. Klapper J. Headache in Sturge-Weber syndrome. Headache. 1994 34, 521-522.
16. Kossoff EH, Bachur CD, Quain AM, Ewen JB, Comi AM. EEG evolution in Sturge-Weber syndrome. Epilepsy Res. 2014 108, 816-819.
17. Kossoff EH, Ferenc L, Comi AM. An infantile-onset, severe, yet sporadic seizure pattern is common in Sturge-Weber syndrome. Epilepsia. 2009 50, 2154-2157.
18. Kramer U, Kahana E, Shorer Z, Ben-Zeev B. Outcome of infants with unilateral Sturge-Weber syndrome and early onset seizures. Dev Med Child Neurol. 2000 42, 756-759.
19. Lance EI, Lanier KE, Zabel TA, Comi AM. Stimulant use in patients with Sturge-Weber syndrome: safety and efficacy. Pediatric Neurology. 2014 51(5), 675-80.
20. Lance EI, Sreenivasan AK, Zabel TA, Kossoff EH, Comi AM. Aspirin use in Sturge-Weber syndrome: side effects and clinical outcomes. J Child Neurol. 2013 28, 213-8.
21. Lee JS, Asano E, Muzik O, Chugani DC, Juhasz C, Pfund Z, Philip S, Behen M, Chugani HT. Sturge-Weber syndrome: correlation between clinical course and FDG PET findings. Neurology. 2001 57,189-195.
22. Lin DD, Barker PB, Hatfield LA, Comi AM. Dynamic MR perfusion and proton MR spectroscopic imaging in Sturge-Weber syndrome: correlation with neurological symptoms. J Magn Reson Imaging. 2006 24, 274-281.
23. Lin DD, Barker PB, Kraut MA, Comi AM. Early characteristics of Sturge-Weber syndrome shown by perfusion MR imaging and proton MR spectroscopic imaging. American Journal of Neuroradiology. 2003 24(9), 1912-15.
24. Marler JJ, Fishman SJ, Kilroy SM, Fang J, Upton J, Mulliken JB, Burrows PE, Zurakowski D, Folkman J, Moses MA. Increased expression of urinary matrix metalloproteinases parallels the extent and activity of vascular anomalies. Pediatrics. 2005 116, 38-45.
25. Mitsuhashi Y, Odermatt BF, Schneider BV, Schnyder UW. Immunohistological evaluation of endothelial markers and basement membrane components in port-wine stains. Dermatologica. 1988 176, 243-250.
26. Pories SE, Zurakowski D, Roy R, Lamb CC, Raza S, Exarhopoulos A, Scheib RG, Schumer S, Lenahan C, Borges V, et al. Urinary metalloproteinases: noninvasive biomarkers for breast cancer risk assessment. Cancer Epidemiol Biomarkers Prev. 2008 17, 1034-1042.
27. Rhoten RL, Comair YG, Shedid D, Chyatte D, Simonson MS. Specific repression of the preproendothelin-1 gene in intracranial arteriovenous malformations. J Neurosurg. 1997 86, 101-108.
28. Rydh M, Malm M, Jernbeck J, Dalsgaard CJ. Ectatic blood vessels in port-wine stains lack innervation: possible role in pathogenesis. Plast Reconstr Surg. 1991 87, 419-422.
29. Shirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP, Cohen B, North PE, Marchuk DA, Comi AM, Pevsner J. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013 368, 1971-1979.
30. Smith ER, Zurakowski D, Saad A, Scott RM, Moses MA. Urinary biomarkers predict brain tumor presence and response to therapy. Clin Cancer Res. 2008 14, 2378-2386.
31. Sreenivasan AK, Bachur CD, Lanier KE, Curatolo AS, Connors SM, Moses MA, Comi AM. Urine vascular biomarkers in Sturge-Weber syndrome. Vasc Med. 2013 18, 122–128.
32. Tallman B, Tan OT, Morelli JG, Piepenbrink J, Stafford TJ, Trainor S, Weston WL. Location of port-wine stains and the likelihood of ophthalmic and/or central nervous system complications. Pediatrics. 1991 87, 323-327.
33. Turin E, Grados MA, Tierney E, Ferenc LM, Zabel A, Comi AM. Behavioral and psychiatric features of Sturge-Weber syndrome. J Nerv Ment Dis. 2010 198, 905-913.

HHT is an autosomal dominant disease with an estimated prevalence of 1/5000¹ and is thought to be present in all races and parts of the world. Though epistaxis is the most common symptom of HHT and mucocutaneous telangiectasia the most common sign², HHT is also frequently complicated by the presence of arteriovenous malformations (AVMs) in the brain, lung, gastrointestinal (GI) tract and liver.

Making the diagnosis of HHT in a patient allows for the appropriate screening and preventative treatment for the patient and their affected family members. HHT has traditionally been diagnosed on the basis of its clinical features but can now also be diagnosed using genetic testing. The clinical diagnostic criteria³ for HHT are detailed in the Table. The clinical diagnosis is considered “definite” if three or more criteria are present, "possible" if 2 criteria are present and “uncertain” when only one criterion is present³. Disease expression is age-related, with an average age of onset for epistaxis of 12 years, with nearly 100% affected by age 40 years^{2, 4-6}. Most patients report the appearance of telangiectasia of the mouth, face or hands 5-30 years after the onset of nosebleeds; most commonly during the third decade. The goal of genetic testing for HHT is to clarify the specific HHT mutation in an HHT family, allowing diagnosis among those relatives (often children and young adults) who do not yet meet clinical diagnostic criteria, but may have unrecognized organ AVMs. Genetic testing is performed first on the index case, for mutations in the endoglin gene (ENG) and the activin A receptor type II-like 1 gene (ACVRL1). Mutations in these genes account for the majority of cases of HHT. At least two other HHT loci have been described, though specific genes at these loci are not yet identified^{7, 8}. Mutations in the SMAD4 gene can cause a rare syndrome of combined juvenile polyposis and HHT⁹.

HHT is associated with cerebral vascular malformations, primarily brain AVMs (BAVMs), in 5-23%. The bleeding risk of BAVMs in HHT has been estimated retrospectively at approximately 0.5% per year¹⁰, though there are no prospective natural history studies. In larger series of sporadic BAVMs¹¹, the annual rate of rupture is 2-4%/year¹¹. Asymptomatic screening for BAVMs has been recommended for HHT patients and is routinely performed across North America, though there is less consensus internationally¹². The goal of treatment is to obliterate the BAVM in order to eliminate the future risk of hemorrhage. Although current treatments may provide a large relative risk reduction for cerebral bleeding, procedural risks are significant. There are no published studies of the efficacy or safety of any form of treatment of BAVMs in HHT patients. However, there are several large case series of embolization, microsurgery and stereotactic radiation in non-HHT BAVMs, showing effectiveness for these modalities, though widely ranging^13-26. Based on this non-HHT literature, these treatment modalities are all considered likely effective treatment strategies, alone or in combination, for HHT BAVMs. However, given the rarity of BAVMs and the associated risks of treatment, the International HHT Guidelines¹² recommended that each case should be managed in an individualized manner and that decisions about invasive testing and therapy should occur at centers with significant experience and expertise in all treatment modalities.

PAVMs are present in approximately 15-50% of people with HHT^{27, 28}. PAVMs have been shown to be associated with disabling and life-threatening complications, such as stroke, TIA, cerebral abscess, massive hemoptysis and spontaneous hemothorax^{27, 29-32} in retrospective series. The neurologic complications are presumed to occur via paradoxical embolization through PAVMs whereas the hemorrhagic complications occur due to spontaneous PAVM rupture. These complications have been demonstrated in largely adult series of HHT patients, though they have also been demonstrated in pediatric HHT series^33-35, albeit smaller in size. There have also been small series reporting these same complications during pregnancy^{36, 37} and the complication risk appears to be greater during pregnancy. The International HHT Guidelines recommended routine screening all HHT patients for PAVMs, with contrast echocardiography, and preventative treatment with transcatheter embolotherapy¹².

Recurrent spontaneous epistaxis is the most common symptom of HHT and often leads to iron-deficiency anemia³⁸. Epistaxis appears before the age of 20 years in about 50% of patients, with 78 – 96 % of all HHT patients developing it eventually². Non-invasive management of chronic recurrent epistaxis in HHT has focused to date on prevention of epistaxis events through measures to maintain integrity of the nasal mucosa, such as humidification. Procedural therapies for chronic HHT-related epistaxis include endonasal laser, electrical or chemical coagulation techniques, replacement of the fragile endonasal mucosa by skin or buccal mucosa (dermoplasty), nasal artery embolization and closure of the nasal cavity (known as Young’s procedure). There have been no controlled or well-designed comparative studies of any of these procedures in HHT-related epistaxis, for either acute or chronic management. The International HHT Guidelines¹² recommended endonasal coagulation as a first approach, if surgical management is deemed necessary, but also recommended that patients considering surgical management consult an otorhinolarnygologist with HHT expertise, given the likely need for recurrent procedures for this chronic symptom and the risks of surgical management in these cases. There are no well-designed studies of the first-line management of acute epistaxis in HHT. The International HHT Guidelines¹² did, however, recommend that the treatment for acute epistaxis requiring intervention include packing with material or products that have a low likelihood of causing re-bleeding with removal (e.g., lubricated low-pressure pneumatic packing).

Although 80% of patients with HHT have gastric or small intestinal telangiectasia³⁹ on endoscopy or capsule examination, only 25-30% of patients will develop symptomatic GI bleeding^{1, 2, 40, 41} which usually does not present until the fifth or sixth decades of life. Patients rarely develop significant GI bleeding before 40 years of age^{1, 2, 40, 41}. Women are affected with GI bleeding in a ratio of 2-3:1^{42, 43}. Patients with HHT and GI bleeding may or may not be symptomatic, as the bleeding is usually in a slow, chronic and intermittent fashion, often without notable melena. Patients often have few symptoms until they become anemic. In severe cases, HHT GI bleeding causes morbidity, dependency on blood transfusions and increased mortality⁴².

Esophagogastroduodenoscopy is the recommended initial test for evaluation of GI bleeding in HHT patients with anemia or iron deficiency, particularly when out of keeping with the severity of epistaxis. Though the majority of patients with HHT will have GI telangiectasia, the utility of endoscopic evaluation is in the anemic or iron-deficient patient. The International HHT Guidelines¹² recommended aggressive management of anemia and iron deficiency, with consideration of limited endoscopic therapy and potential medical therapies (hormonal therapy, anitfibrinolytics) in refractory cases, though evidence is limited.

Liver VMs are present in 32-78% of HHT patients^44-48 (See Table). Though there is no published natural history data regarding liver VMs in HHT, it appears that symptoms occur in only about 8% of the patients with HHT and liver VMs^{46, 49}. The clinical presentations of liver VMs include high-output heart failure, portal hypertension and biliary necrosis, as detailed in a recent review⁵⁰. In patients who have symptoms suggestive of liver VMs⁵⁰, Doppler ultrasound or triphasic hepatic CT can be used to confirm the diagnosis. There are uncontrolled case series of treatments of liver VMs, specifically hepatic artery embolization and liver transplantation. Hepatic artery embolization has the objective of reducing arteriovenous or arterioportal shunting by embolizing branches of the hepatic artery. Embolization appears to be effective in improving symptoms related to high output heart failure and mesenteric steal syndrome⁵¹, however, the effect is transient and symptoms generally recur. More importantly, ischemic complications (ischemic cholangitis, ischemic cholecystitis and/or hepatic necrosis) leading to transplant or death occur in approximately 30% of the treated cases, including 50% of treated portal hypertension cases⁵¹. The 2-year survival with embolization was approximately 73%. With liver transplantation, symptoms resolved in the majority of patients^{52, 53}. Liver transplantation is associated with high blood transfusion requirements, prolonged hospital stay and a relatively high rate of postoperative complications. However, the reported 5-year survival rate of 83% in the larger series⁵³ compared favorably to overall survival rates for liver transplantation. The International HHT Guidelines recommended that referral for liver transplantation be considered in patients with liver VMs that develop ischemic biliary necrosis, intractable heart failure or intractable portal hypertension. Though there are no controlled studies to date, there is growing interest in antiangiogenic therapy in HHT, with recent case reports of clinical response to antiangiogeneic therapy^54-56, and even with improvement in symptoms from liver VMs⁵⁵.

Diagnostic Criteria (Curaçao Criteria) for clinical diagnosis of HHT

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