HHT2

Hereditary hemorrhagic telangiectasia type 2 (HHT2) is caused by mutation in the ACVRL1 gene (MIM.601284 or ALK1) on chromosome 12q.

Visceral findings of HHT2 included pulmonary arteriovenous malformations (PAVMs) (6%), cerebral AVM (7%), spinal AVM (3%), hepatic AVM (17%), gastrointestinal bleeding due to AVMs (11%), and cirrhosis (3%).

Seventy-two percent of patients had onset of nosebleeds by age 15 years; however, there was overlap in frequency of epistaxis between mutation-negative and mutation-positive individuals. The findings illustrated the extreme phenotypic variability of HHT2 even in those with the same mutation.

Pulmonary hypertension that is clinically and histologically indistinguishable from primary pulmonary hypertension (MIM.178600) has been reported in a subset of patients with hereditary hemorrhagic telangiectasia.

Synopsis

 Conjunctival telangiectases
 Spontaneous, recurrent epistaxis (onset in childhood)
 Lip telangiectases
 Tongue telangiectases
 Palate telangiectases
 Nasal mucosa telangiectases
 Right-to-left shunt
Right-to-left shunt
 Cirrhosis
 Liver arteriovenous malformation
 Gastrointestinal hemorrhage (onset usually 5th-6th decade)
 Angiodysplasia
 Arteriovenous malformation
 Telangiectases (stomach, duodenum, small bowel, colon)
 Melena
 Hematochezia
 Hematemesis
 Nail bed telangiectases
 Fingerpad telangiectases
 Clubbin
 Telangiectases (especially on tongue, lips, palate, face, conjunctiva, trunk, nail beds, fingers, and finger pads)
 Migraine headache
 Brian abscess
 Transient ischemic attack
 Ischemic stroke
 Seizure
 Intracerebral hemorrhage
 Subarachnoid hemorrhage
 Cerebral arteriovenous malformation
 Spinal arteriovenous malformation
 Polycythemia
 Definite diagnosis if 3/4 criteria present (epistaxis, telangiectasia, visceral lesion, or family history)
 Genetic heterogeneity. See HHT1 (187300) caused by mutations in endoglin (ENG, 131195)
 PAVM more frequent in HHT1 than HHT2
 Anemia
 Caused by mutations in the activin receptor-like kinase gene (ALK1, 601284.0001)

References

 Lesca, G., Genin, E., Blachier, C., Olivieri, C., Coulet, F., Brunet, G., Dupuis-Girod, S., Buscarini, E., Soubrier, F., Calender, A., Danesino, C., Giraud, S., Plauchu, H. Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients. Europ. J. Hum. Genet. 16: 742-749, 2008. [PubMed: 18285823]

 Brakensiek, K., Frye-Boukhriss, H., Malzer, M., Abramowicz, M., Bahr, M. J., von Beckerath, N., Bergmann, C., Caselitz, M., Holinski-Feder, E., Muschke, P., Oexle, J., Strobl-Wildemann, G., Wolff, G., El-Harith, E. A., Stuhrmann, M. Detection of a significant association between mutations in the ACVRL1 gene and hepatic involvement in German patients with hereditary haemorrhagic telangiectasia. Clin. Genet. 74: 171-177, 2008. [PubMed: 18498373]

 Olivieri, C., Pagella, F., Semino, L., Lanzarini, L., Valacca, C., Pilotto, A., Corno, S., Scappaticci, S., Manfredi, G., Buscarini, E., Danesino, C. Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. J. Hum. Genet. 52: 820-829, 2007. [PubMed: 17786384]

 Wehner, L.-E., Folz, B. J., Argyriou, L., Twelkemeyer, S., Teske, U., Geisthoff, U. W., Werner, J. A., Engel, W., Nayernia, K. Mutation analysis in hereditary haemorrhagic telangiectasia in Germany reveals 11 novel ENG and 12 novel ACVRL1/ALK1 mutations. Clin. Genet. 69: 239-245, 2006. [PubMed:16542389]

 Abdalla, S. A., Geisthoff, U. W., Bonneau, D., Plauchu, H., McDonald, J., Kennedy, S., Faughnan, M. E., Letarte, M. Visceral manifestations in hereditary haemorrhagic telangiectasia type 2. J. Med. Genet. 40: 494-502, 2003. [PubMed: 12843319]

 Abdalla, S. A., Pece-Barbara, N., Vera, S., Tapia, E., Paez, E., Bernabeu, C., Letarte, M. Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2. Hum. Molec. Genet. 9: 1227-1237, 2000. [PubMed: 10767348]

 Johnson, D. W., Berg, J. N., Gallione, C. J., McAllister, K. A., Warner, J. P., Helmbold, E. A., Markel, D. S., Jackson, C. E., Porteous, M. E. M., Marchuk, D. A. A second locus for hereditary hemorrhagic telangiectasia maps to chromosome 12. Genome Res. 5: 21-28, 1995. [PubMed: 8717052]