Angioedema hereditary 8 D81.4

Comment: Knowledge of rare genetic diseases such as hereditary angioedema (HAE) has evolved in parallel with the development of new molecular tools. C1 inhibitor (C1-INH) deficiency has been recognized as the major cause of HAE (HAE-C1-INH) since the 1960s. Discovery of the broad spectrum of mutations affecting the C1-INH gene(SERPING1) was not possible until the late 1980s, when Sanger sequencing became available and more accessible worldwide.

However, the involvement of other genes in HAE was not discovered until 2006 with the description of mutations in the F12 gene in patients with HAE and normal C1-INH. The knowledge gained through the new era of genomics has been crucial for the discovery of mutations in additional genes, improving or explaining the understanding of the complex pathogenesis of this phenotypically largely identical disease. In the last three years, advanced next-generation sequencing techniques have enabled the identification of mutations in five additional novel genes associated with hereditary angioedema variants with normal C1-INH (nC1-INH-HAE): ANGPT1 (angiopoietin-1), PLG (plasminogen), KNG1 (kininogen), MYOF (myoferlin), and HS3ST6 (heparan sulfate glucosamine 3-O-sulfotransferase 6).

Hereditary angioedema-8 (HAE8) is an autosomal dominant disorder clinically characterized by recurrent and self-limited episodes of localized edema in various organs, including the face, tongue, larynx, and extremities. In rare cases, swelling of the tongue or larynx can lead to airway obstruction. Abdominal attacks may also occur, manifested by abdominal pain, vomiting, and diarrhea. The condition results from increased vascular permeability (Bork et al. 2021).

Caused by a "missense mutation" in the HS3ST6 gene (T144S; 619210.0001).

2 and 3rd decade of life (12-20 years)

Bork et al (2021) reported on 4 women in a multigenerational family who developed HAE between 12 and 20 years of age. They suffered from episodic swelling, usually of the face and lips, and sometimes laryngeal and tongue swelling. Patients also had abdominal attacks with painful cramps, vomiting, and diarrhea. Evidence in two patients was provocation of angioedema by estrogen. Other triggering factors included dental work, tongue bites, and gardening. One patient reported 5 spontaneous abortions.

In three affected women from a multigenerational family with HAE8, Bork et al (2021) identified a heterozygous missense mutation in the HS3ST6 gene (T144S; 619210.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Noting the role of this gene in substrate-specific O-sulfation of noncoagulant heparan sulfate to coagulant heparan sulfate, the authors suggested that the mutation might impair cell surface binding of the kallikrein precursor or its internalization by endocytosis, leading to increased cleavage, overproduction of bradykinin, and increased vascular permeability. This would set the stage for the development of angioedema.

1. Bork K et al (2021) Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation. J Allergy Clin Immun 148: 1041-1048.
2. Farkas H et al (2021) Screening for plasminogen mutations in hereditary angioedema patients. Genes (Basel) 12: 402.