MRE11 and HHT: No Established Clinical Association
There is no established clinical relationship between MRE11 (Meiotic Recombination 11) mutations and Hereditary Hemorrhagic Telangiectasia (HHT), and MRE11 is not a causative gene for HHT.
Genetic Basis of HHT
The causative genes for HHT are well-defined and do not include MRE11:
- ENG (endoglin) mutations cause HHT type 1, identified in approximately 54% of HHT families 1
- ACVRL1 (ALK-1) mutations cause HHT type 2, identified in approximately 43% of HHT families 1
- SMAD4 mutations cause juvenile polyposis-HHT overlap syndrome, occurring in 1-2% of HHT cases 1
- GDF2 mutations account for a small number of additional cases 2
Together, ENG and ACVRL1 mutations account for approximately 96% of individuals meeting strict Curaçao diagnostic criteria 1, 2
MRE11 Context
MRE11 is a DNA repair gene involved in double-strand break repair and homologous recombination. It is not part of the TGF-β signaling pathway that underlies HHT pathophysiology 3, 4. MRE11 mutations are associated with ataxia-telangiectasia-like disorder (ATLD), which is a distinct condition from HHT with different clinical features, inheritance patterns, and management approaches.
If You Suspect HHT: Diagnostic Approach
If the clinical question involves a patient with telangiectasias or suspected HHT:
- Apply Curaçao criteria: Diagnosis requires 3 of 4 features (spontaneous recurrent epistaxis, multiple telangiectasias at characteristic sites, visceral lesions, first-degree relative with HHT) 1
- Order genetic testing for ENG, ACVRL1, and SMAD4 simultaneously with deletion/duplication analysis, which identifies causative mutations in 97% of patients with definite clinical diagnosis 1
- Screen for visceral arteriovenous malformations: Perform contrast echocardiography or chest CT for pulmonary AVMs, brain MRI for cerebral AVMs, and Doppler ultrasonography for hepatic involvement 1
Critical Management Points for Confirmed HHT
- Never perform liver biopsy in HHT patients due to catastrophic hemorrhage risk 1, 5
- Refer to multidisciplinary HHT center for coordinated screening and management 1
- Stepwise treatment for epistaxis: Begin with nasal moisturization, escalate to oral tranexamic acid, then local ablative therapies, and reserve systemic bevacizumab for refractory cases 6
- SMAD4 carriers require intensive GI surveillance starting at age 18 years every 1-3 years due to 73% prevalence of gastric polyposis and exclusive occurrence of gastric cancers in this subgroup 1