Special types — HHT · Osler’s disease

Ocular manifestations occur frequently, in 45–65% of patients with HHT. The most common (in 35–42% of cases) is hemorrhagic lacrimation resulting from conjunctival teleangiectasias. The prevalence of retinal teleangiectasias has been reported in the past to be only about 2–10%, based on slit lamp examination and funduscopy. Recent studies using fluorescence angiography (FA) and OCT angiography (OCTA) revealed that the majority of HHT patients (78%; mean age 52.3 years) have fine peripheral teleangiectasias of the temporal or nasal retina. Retinal teleangiectasias are thought to be a common, to regular, late manifestation. Because of the risk of hemorrhage with potential vision loss, ophthalmologic checkup using fluorescence angiography is recommended.

The prevalence of migraine compared to the general population (9.8%) is elevated at 38–39.6%. Pathophysiologically, a vasculopathy as a consequence of impaired TGF-ß signaling (proinflammatory effect of TGF-ß1?) is discussed, independent of the presence of pulmonary or cerebral shunts. HHT patients with pulmonary AVM (pAVM) tend to have migraine with aura, whereas patients without pulmonary AVM more often have migraine without aura.

Patients with HHT have an increased risk of developing bacterial infections. The cause is thought to be impairment of the antibacterial functions of neutrophils in HHT patients.

Coagulation disorders should be ruled out as additional risk factors in HHT patients. Bleeding (epistaxis and gastrointestinal bleeding) may lead to iron deficiency anemia. Iron deficiency is probably partly responsible for an increased tendency to thrombosis. The combination of HHT with a blood coagulation disorder (e.g., hemophilia, in which bleeding occurs after minor trauma and spontaneously) can lead to bleeding events with dramatic manifestations.

In juvenile polyposis-HHT (JPHT) overlap syndrome based on SMAD4 mutations, polyps of the gastrointestinal tract are prominent (they can occur as early as infancy). About three quarters of SMAD4 mutation carriers show features of HHT. As an initial manifestation, features of HHT are rare. Almost all patients have polyps of the colon and 70% have polyps of the stomach. The risk of malignancy (lifetime risk) is 40% for colon carcinoma and 20% for gastric carcinoma. Compared to other syndromes with juvenile polyposis, the upper gastrointestinal tract is more often affected in JPHT syndrome.

Patients with Osler’s syndrome without molecular genetic findings should be asked about polyposis/intestinal cancer, including in family members, and if necessary appropriate diagnostic investigation should be offered.

The diagnosis of familial juvenile polyposis is first made clinically. The diagnosis is suspected if at least five juvenile polyps are found in a patient, if juvenile polyps are detected outside the colon, or if other family members are known to have juvenile polyps and the patient is found to have a juvenile polyp.

Conversely, all JPHT patients with SMAD4 mutation should be screened for HHT manifestations.

Mutations in numerous genes of the TGF-ß signaling pathway are associated with aortopathies. Of the HHT genes (same pathway),  mutations in SMAD4-Ges are associated with a significant risk of aortic root dilatation. Patients with a SMAD4 mutation therefore require imaging evaluation for manifestation of aortopathy.