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Hereditary hemorrhagic telangiectasia type 4(HHT4)

MedGen UID:
341824
Concept ID:
C1857688
Disease or Syndrome
Synonym: HHT4
 
Monarch Initiative: MONDO:0012532
OMIM®: 610655

Disease characteristics

Excerpted from the GeneReview: Hereditary Hemorrhagic Telangiectasia
Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. The most common clinical manifestation is spontaneous and recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Telangiectases (small AVMs) are characteristically found on the lips, tongue, buccal and gastrointestinal (GI) mucosa, face, and fingers. The appearance of telangiectases is generally later than epistaxis but may be during childhood. Large AVMs occur most often in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic. A minority of individuals with HHT have GI bleeding, which is rarely seen before age 50 years. [from GeneReviews]
Authors:
Jamie McDonald  |  David A Stevenson   view full author information

Clinical features

From HPO
Transient ischemic attack
MedGen UID:
853
Concept ID:
C0007787
Disease or Syndrome
A brief attack (from a few minutes to an hour) of cerebral dysfunction of vascular origin, with no persistent neurological deficit.
Spinal arteriovenous malformation
MedGen UID:
83876
Concept ID:
C0348023
Congenital Abnormality
Right-to-left shunt
MedGen UID:
98446
Concept ID:
C0428871
Finding
Pattern of blood flow in the heart that deviates from the normal circuit of the circulatory system from the right side of the heart to the left.
High-output congestive heart failure
MedGen UID:
196646
Concept ID:
C0742747
Disease or Syndrome
A form of heart failure characterized by elevated cardiac output. This may be seen in patients with heart failure and hyperthyroidism, anemia, pregnancy, arteriovenous fistulae, and others.
Cerebral arteriovenous malformation
MedGen UID:
214590
Concept ID:
C0917804
Congenital Abnormality
Arteriovenous malformations of the brain are tortuous, morphologically abnormal vascular channels between arteries and veins that lack an intervening capillary network, allowing high-pressure arterial blood from feeding arteries to shunt directly into the venous outflow system. These vascular malformations occur in approximately 15 per 100,000 persons and are a leading cause of hemorrhagic stroke in young adults and children (summary by Nikolaev et al., 2018).
Pulmonary arteriovenous malformation
MedGen UID:
341826
Concept ID:
C1857690
Anatomical Abnormality
Pulmonary arteriovenous malformation, a condition most commonly associated with hereditary hemorrhagic telangiectasia, is an abnormal communication between the pulmonary artery and pulmonary vein without an intervening capillary communication. HRCT images usually show a coarse spidery appearance of the peripheral vascular markings in the lungs. More specific findings are obtained in the pulmonary angiogram where the normally invisible capillary phase is replaced by irregular vascular channels bridging the peripheral branches of pulmonary arteries and veins.
Venous varicosities of celiac and mesenteric vessels
MedGen UID:
341828
Concept ID:
C1857692
Finding
Elongated and tortuous mesenteric veins, which comprise the inferior mesenteric vein and the superior mesenteric vein.
Arteriovenous fistulas of celiac and mesenteric vessels
MedGen UID:
387886
Concept ID:
C1857693
Anatomical Abnormality
Cerebral hemorrhage
MedGen UID:
423648
Concept ID:
C2937358
Pathologic Function
Hemorrhage into the parenchyma of the brain.
Dilatation of mesenteric artery
MedGen UID:
1381896
Concept ID:
C4476552
Anatomical Abnormality
Abnormal outpouching or sac-like dilatation in the wall of the inferior mesenteric artery or superior mesenteric artery .
Dilatation of celiac artery
MedGen UID:
1393390
Concept ID:
C4477059
Anatomical Abnormality
Abnormal outpouching or sac-like dilatation in the wall of the celiac artery.
Subarachnoid hemorrhage
MedGen UID:
11625
Concept ID:
C0038525
Disease or Syndrome
Hemorrhage occurring between the arachnoid mater and the pia mater.
Migraine
MedGen UID:
57451
Concept ID:
C0149931
Disease or Syndrome
Migraine is a chronic neurological disorder characterized by episodic attacks of headache and associated symptoms.
Ischemic stroke
MedGen UID:
215292
Concept ID:
C0948008
Disease or Syndrome
A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. It is said to be the third leading cause of death in the United States. Gunel and Lifton (1996) noted that about 20% of strokes are hemorrhagic, resulting in bleeding into the brain. Ischemic strokes, resulting from vascular occlusion, account for the majority of strokes. Bersano et al. (2008) reviewed genetic polymorphisms that have been implicated in the development of stroke. Candidate genes include those involved in hemostasis (see, e.g., F5; 612309), the renin-angiotensin-aldosterone system (see, e.g., ACE; 106180), homocysteine (see, e.g., MTHFR; 607093), and lipoprotein metabolism (see, e.g., APOE; 107741). See also hemorrhagic stroke, or intracerebral hemorrhage (ICH; 614519).
Spontaneous, recurrent epistaxis
MedGen UID:
816045
Concept ID:
C3809715
Finding
Dyspnea
MedGen UID:
3938
Concept ID:
C0013404
Sign or Symptom
Difficult or labored breathing. Dyspnea is a subjective feeling only the patient can rate, e.g., on a Borg scale.
Tongue telangiectasia
MedGen UID:
871382
Concept ID:
C4025878
Anatomical Abnormality
Telangiectasia (that is, the presence of small dilated superficial blood vessels) of the tongue.
Cyanosis
MedGen UID:
1189
Concept ID:
C0010520
Sign or Symptom
Bluish discoloration of the skin and mucosa due to poor circulation or inadequate oxygenation of arterial or capillary blood.
Conjunctival telangiectasia
MedGen UID:
66780
Concept ID:
C0239105
Disease or Syndrome
The presence of small (ca. 0.5-1.0 mm) dilated blood vessels near the surface of the mucous membranes of the conjunctiva.
Lip telangiectasia
MedGen UID:
347522
Concept ID:
C1857697
Finding
Telangiectasia (that is, the presence of small dilated superficial blood vessels) of the lips.
Palate telangiectasia
MedGen UID:
387887
Concept ID:
C1857699
Finding
The presence of small (ca. 0.5-1.0 mm) dilated blood vessels near the surface of the mucous membranes of the palate.
Nasal mucosa telangiectasia
MedGen UID:
871359
Concept ID:
C4025853
Finding
Telangiectasia of the nasal mucosa.

Professional guidelines

PubMed

Pollak M, Gatt D, Shaw M, Hewko SL, Lamanna A, Santos S, Ratjen F
J Pediatr 2023 Dec;263:113665. Epub 2023 Aug 11 doi: 10.1016/j.jpeds.2023.113665. PMID: 37572862
Tunkel DE, Anne S, Payne SC, Ishman SL, Rosenfeld RM, Abramson PJ, Alikhaani JD, Benoit MM, Bercovitz RS, Brown MD, Chernobilsky B, Feldstein DA, Hackell JM, Holbrook EH, Holdsworth SM, Lin KW, Lind MM, Poetker DM, Riley CA, Schneider JS, Seidman MD, Vadlamudi V, Valdez TA, Nnacheta LC, Monjur TM
Otolaryngol Head Neck Surg 2020 Jan;162(1):8-25. doi: 10.1177/0194599819889955. PMID: 31910122
Tunkel DE, Anne S, Payne SC, Ishman SL, Rosenfeld RM, Abramson PJ, Alikhaani JD, Benoit MM, Bercovitz RS, Brown MD, Chernobilsky B, Feldstein DA, Hackell JM, Holbrook EH, Holdsworth SM, Lin KW, Lind MM, Poetker DM, Riley CA, Schneider JS, Seidman MD, Vadlamudi V, Valdez TA, Nnacheta LC, Monjur TM
Otolaryngol Head Neck Surg 2020 Jan;162(1_suppl):S1-S38. doi: 10.1177/0194599819890327. PMID: 31910111

Suggested Reading

PubMed

Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, Kjeldsen AD, Plauchu H
Am J Med Genet 2000 Mar 6;91(1):66-7. doi: 10.1002/(sici)1096-8628(20000306)91:1<66::aid-ajmg12>3.0.co;2-p. PMID: 10751092

Recent clinical studies

Etiology

Gaines JJ, Gilbert BC, Gossage JR, Parker W, Reddy A, Forseen SE
AJNR Am J Neuroradiol 2022 Nov;43(11):1603-1607. Epub 2022 Oct 20 doi: 10.3174/ajnr.A7677. PMID: 36265891Free PMC Article
Bofarid S, Hosman AE, Mager JJ, Snijder RJ, Post MC
Int J Mol Sci 2021 Mar 27;22(7) doi: 10.3390/ijms22073471. PMID: 33801690Free PMC Article
Shovlin CL, Simeoni I, Downes K, Frazer ZC, Megy K, Bernabeu-Herrero ME, Shurr A, Brimley J, Patel D, Kell L, Stephens J, Turbin IG, Aldred MA, Penkett CJ, Ouwehand WH, Jovine L, Turro E
Blood 2020 Oct 22;136(17):1907-1918. doi: 10.1182/blood.2019004560. PMID: 32573726Free PMC Article
Tunkel DE, Anne S, Payne SC, Ishman SL, Rosenfeld RM, Abramson PJ, Alikhaani JD, Benoit MM, Bercovitz RS, Brown MD, Chernobilsky B, Feldstein DA, Hackell JM, Holbrook EH, Holdsworth SM, Lin KW, Lind MM, Poetker DM, Riley CA, Schneider JS, Seidman MD, Vadlamudi V, Valdez TA, Nnacheta LC, Monjur TM
Otolaryngol Head Neck Surg 2020 Jan;162(1_suppl):S1-S38. doi: 10.1177/0194599819890327. PMID: 31910111
Labeyrie PE, Courthéoux P, Babin E, Bergot E, Touzé E, Pelage JP
J Neuroradiol 2016 Jul;43(4):236-45. Epub 2016 Apr 5 doi: 10.1016/j.neurad.2016.02.005. PMID: 27059009

Diagnosis

Aguilera C, Padró-Miquel A, Esteve-Garcia A, Cerdà P, Torres-Iglesias R, Llecha N, Riera-Mestre A
Genes (Basel) 2023 Mar 22;14(3) doi: 10.3390/genes14030772. PMID: 36981042Free PMC Article
Kitayama K, Ishiguro T, Komiyama M, Morisaki T, Morisaki H, Minase G, Hamanaka K, Miyatake S, Matsumoto N, Kato M, Takahashi T, Yorifuji T
BMC Med Genomics 2021 Dec 6;14(1):288. doi: 10.1186/s12920-021-01139-y. PMID: 34872578Free PMC Article
Tunkel DE, Anne S, Payne SC, Ishman SL, Rosenfeld RM, Abramson PJ, Alikhaani JD, Benoit MM, Bercovitz RS, Brown MD, Chernobilsky B, Feldstein DA, Hackell JM, Holbrook EH, Holdsworth SM, Lin KW, Lind MM, Poetker DM, Riley CA, Schneider JS, Seidman MD, Vadlamudi V, Valdez TA, Nnacheta LC, Monjur TM
Otolaryngol Head Neck Surg 2020 Jan;162(1_suppl):S1-S38. doi: 10.1177/0194599819890327. PMID: 31910111
Major T, Gindele R, Szabó Z, Kis Z, Bora L, Jóni N, Bárdossy P, Rácz T, Bereczky Z
Pathol Oncol Res 2020 Oct;26(4):2783-2788. Epub 2019 Jan 26 doi: 10.1007/s12253-019-00602-7. PMID: 30685840
Labeyrie PE, Courthéoux P, Babin E, Bergot E, Touzé E, Pelage JP
J Neuroradiol 2016 Jul;43(4):236-45. Epub 2016 Apr 5 doi: 10.1016/j.neurad.2016.02.005. PMID: 27059009

Therapy

Wu V, Kell E, Faughnan ME, Lee JM
Laryngoscope 2021 Mar;131(3):E689-E693. Epub 2020 Jun 18 doi: 10.1002/lary.28824. PMID: 32557619
Tunkel DE, Anne S, Payne SC, Ishman SL, Rosenfeld RM, Abramson PJ, Alikhaani JD, Benoit MM, Bercovitz RS, Brown MD, Chernobilsky B, Feldstein DA, Hackell JM, Holbrook EH, Holdsworth SM, Lin KW, Lind MM, Poetker DM, Riley CA, Schneider JS, Seidman MD, Vadlamudi V, Valdez TA, Nnacheta LC, Monjur TM
Otolaryngol Head Neck Surg 2020 Jan;162(1_suppl):S1-S38. doi: 10.1177/0194599819890327. PMID: 31910111
Zhao Y, Zhang Y, Wang X, Zhang L
Mol Genet Genomic Med 2019 Sep;7(9):e893. Epub 2019 Aug 10 doi: 10.1002/mgg3.893. PMID: 31400083Free PMC Article
Desroches-Castan A, Tillet E, Ricard N, Ouarné M, Mallet C, Belmudes L, Couté Y, Boillot O, Scoazec JY, Bailly S, Feige JJ
Hepatology 2019 Oct;70(4):1392-1408. Epub 2019 May 31 doi: 10.1002/hep.30655. PMID: 30964206
Brinjikji W, Iyer VN, Wood CP, Lanzino G
J Neurosurg 2017 Aug;127(2):302-310. Epub 2016 Oct 21 doi: 10.3171/2016.7.JNS16847. PMID: 27767404

Prognosis

Aguilera C, Padró-Miquel A, Esteve-Garcia A, Cerdà P, Torres-Iglesias R, Llecha N, Riera-Mestre A
Genes (Basel) 2023 Mar 22;14(3) doi: 10.3390/genes14030772. PMID: 36981042Free PMC Article
Bofarid S, Hosman AE, Mager JJ, Snijder RJ, Post MC
Int J Mol Sci 2021 Mar 27;22(7) doi: 10.3390/ijms22073471. PMID: 33801690Free PMC Article
Thompson KP, Nelson J, Kim H, Pawlikowska L, Marchuk DA, Lawton MT, Faughnan ME; Brain Vascular Malformation Consortium HHT Investigator Group
Orphanet J Rare Dis 2021 Jan 6;16(1):12. doi: 10.1186/s13023-020-01579-2. PMID: 33407668Free PMC Article
Shovlin CL, Simeoni I, Downes K, Frazer ZC, Megy K, Bernabeu-Herrero ME, Shurr A, Brimley J, Patel D, Kell L, Stephens J, Turbin IG, Aldred MA, Penkett CJ, Ouwehand WH, Jovine L, Turro E
Blood 2020 Oct 22;136(17):1907-1918. doi: 10.1182/blood.2019004560. PMID: 32573726Free PMC Article
Major T, Gindele R, Szabó Z, Kis Z, Bora L, Jóni N, Bárdossy P, Rácz T, Bereczky Z
Pathol Oncol Res 2020 Oct;26(4):2783-2788. Epub 2019 Jan 26 doi: 10.1007/s12253-019-00602-7. PMID: 30685840

Clinical prediction guides

Aguilera C, Padró-Miquel A, Esteve-Garcia A, Cerdà P, Torres-Iglesias R, Llecha N, Riera-Mestre A
Genes (Basel) 2023 Mar 22;14(3) doi: 10.3390/genes14030772. PMID: 36981042Free PMC Article
Kitayama K, Ishiguro T, Komiyama M, Morisaki T, Morisaki H, Minase G, Hamanaka K, Miyatake S, Matsumoto N, Kato M, Takahashi T, Yorifuji T
BMC Med Genomics 2021 Dec 6;14(1):288. doi: 10.1186/s12920-021-01139-y. PMID: 34872578Free PMC Article
Xu Y, Zhang YB, Liang LJ, Tian JL, Lin JM, Wang PP, Li RH, Gu ML, Gao ZC
BMC Pulm Med 2021 Jun 10;21(1):197. doi: 10.1186/s12890-021-01524-4. PMID: 34112136Free PMC Article
Thompson KP, Nelson J, Kim H, Pawlikowska L, Marchuk DA, Lawton MT, Faughnan ME; Brain Vascular Malformation Consortium HHT Investigator Group
Orphanet J Rare Dis 2021 Jan 6;16(1):12. doi: 10.1186/s13023-020-01579-2. PMID: 33407668Free PMC Article
Shovlin CL, Simeoni I, Downes K, Frazer ZC, Megy K, Bernabeu-Herrero ME, Shurr A, Brimley J, Patel D, Kell L, Stephens J, Turbin IG, Aldred MA, Penkett CJ, Ouwehand WH, Jovine L, Turro E
Blood 2020 Oct 22;136(17):1907-1918. doi: 10.1182/blood.2019004560. PMID: 32573726Free PMC Article

Recent systematic reviews

Brinjikji W, Iyer VN, Wood CP, Lanzino G
J Neurosurg 2017 Aug;127(2):302-310. Epub 2016 Oct 21 doi: 10.3171/2016.7.JNS16847. PMID: 27767404
Brinjikji W, Nasr DM, Cloft HJ, Iyer VN, Lanzino G
Interv Neuroradiol 2016 Jun;22(3):354-61. Epub 2016 Jan 27 doi: 10.1177/1591019915623560. PMID: 26823330Free PMC Article

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