J Korean Med Sci.  2009 Feb;24(1):69-76. 10.3346/jkms.2009.24.1.69.

Clinical Features and Mutations in the ENG, ACVRL1, and SMAD4 genes in Korean Patients with Hereditary Hemorrhagic Telangiectasia

• Lee ST
• Kim JA
• Jang SY
• Kim DK
• Do YS
• Suh GY
• Kim JW
• Ki CS

• KMID: 1794409
• DOI: http://doi.org/10.3346/jkms.2009.24.1.69

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder that is characterized by abnormal communication between the arteries and veins in the skin, mucosa, and various organs. HHT has been reported to show significant phenotypic variability and genetic heterogeneity with wide ethnic and geographic variations. Although mutations in the endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes have been known to cause HHT for more than 10 yr, little is known about the clinical features or genetic background of Korean patients with HHT. In addition, mutations in mothers against decapentaplegic homolog 4 (SMAD4) are also seen in patients with the combined syndrome of juvenile polyposis and HHT. This study examined five Korean patients with the typical manifestations of HHT such as frequent epistaxis and pulmonary arteriovenous malformations. Direct sequencing of the ENG and ACVRL1 genes revealed one known mutation, ENG c.277C>T, in one patient and two novel mutations, ENG c.992-1G>C and ACVRL1 c.81dupT in two patients, respectively. The remaining two patients with negative results were screened for SMAD4 mutations as well as gross deletions of ENG and ACVRL1 using multiple ligation-dependent probe amplification, but none was detected. Despite the small number of patients investigated, we firstly report Korean patients with genetically confirmed HHT, and show the genetic and allelic heterogeneity underlying HHT.

Keyword

Telangiectasia, Hereditary Hemorrhagic; ENG; ACVRL1; SMAD4; Mutation; Korean

MeSH Terms

Activin Receptors, Type II/*genetics
Adult
Alleles
Angiography
Antigens, CD/*genetics
Asian Continental Ancestry Group/*genetics
Base Sequence
Female
Genetic Predisposition to Disease
Humans
Korea
Male
Middle Aged
*Mutation
Pedigree
Receptors, Cell Surface/*genetics
Smad4 Protein/*genetics
Telangiectasia, Hereditary Hemorrhagic/diagnosis/*genetics/pathology
Tomography, X-Ray Computed
Young Adult

Figure

• 

  Fig. 1 Clinical features of the HHT patients: (A) telangiectasia on the periungal regions of the fingers of patient 1, (B) telangiectasia on the lips of patient 1, (C) telangiectasia on the oral mucosa of the father of patient 2, (D) bleeding foci in the Kisselbach's plexus of patient 3; (E) microtelangia on the tongue of patient 5, and (F) clubbing fingers with one small hemangioma in patient 5.

• 

  Fig. 2 Pedigrees of families of (A) patient 1 and (B) patient 2.

• 

  Fig. 3 Radiology findings of the HHT patients. (A) and (B) CT angiography of the liver in patient 1 shows an enlarged celiac axis (arrow), a prominent hepatic artery (arrowhead) with multiple aberrant collateral vessels, and heterogeneous attenuation of the liver. (C) and (D) Abdominal CT of patient 3 shows severe tortuous dilatation of the hepatic artery (arrow) and its intrahepatic branches (arrowhead) with mottled hepatic enhancement.

• 

  Fig. 4 Pulmonary angiography of the HHT patients. (A) a large pulmonary arteriovenous malformation (AVM) in patient 2; (B) a new small-sized pulmonary AVM in the right middle lobe in patient 3; (C) multifocal AVM in patient 4; (D) extensive peripheral AVM in patient 5.

• 

  Fig. 5 Sequencing results of three mutation-positive patients with HHT. (A) ENG c.277C>T (p.Arg93X) in patient 1; (B) ENG c.992-1G>C (splicing defect) in patient 2; (C) ACVRL1 c.81dupT (p. Arg 28SerfsX10) in patient 3.

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