Pediatric Osler-Weber-Rendu Syndrome 

Osler-Weber-Rendu syndrome, also known as hereditary hemorrhagic telangiectasia (HHT), is an autosomal dominant disorder typically identified by the triad of telangiectasia, recurrent epistaxis, and a positive family history for the disorder. The major cause of morbidity and mortality due to this disorder lies in the presence of multiorgan (multiple organ) arteriovenous malformations (AVMs) and the associated hemorrhage that may accompany them.

The disease has a wide spectrum of presentations. Patients may be asymptomatic or have multiple organ involvement presenting at any age.

Treatment consists of management of bleeding via both medical and surgical options, as well as surgical management of arteriovenous malformations and further sequelae. The prognosis varies, depending on the severity of symptoms.

The images below show examples of typical findings in patients with Osler-Weber-Rendu syndrome.

The clinical manifestations of Osler-Weber-Rendu disease are caused by the development of abnormal vasculature, including telangiectasias, AVMs, and aneurysms. The genetic defect largely involves either one of two genes: ENG or ALK-1. Both of these genes transcribe proteins that are highly expressed on endothelial cells and play important roles in tissue repair and angiogenesis through their common function as receptors for transforming growth factor beta.

Defects in the endothelial cell junctions, endothelial cell degeneration, and weakness of the perivascular connective tissue are thought to cause dilation of capillaries and postcapillary venules, which manifest as telangiectasias. Most commonly, telangiectasias involve the mucous membranes, as well as the skin, the conjunctiva, the retina, and the GI tract.

AVMs are abnormal tortuous vessels with both arterial and venous components. Larger AVMs can cause left-to-right shunting and, if sufficiently large, may contribute to high-output heart failure. Loss of the muscularis layer and disturbance of the elastic lamina of vessel walls may also give rise to aneurysms in multiple organ systems. AVMs are found in the lungs, brain, and liver.

Osler-Weber-Rendu syndrome is caused by genetic defects with an autosomal dominant inheritance.^[1] So far, 2 primary loci have been identified: one on chromosome arm 9q33-34 (HHT1) and a second on chromosome arm 12q11-14 (HHT2). Two more genes have been implicated; MADH4 gene mutation in patients with a combined syndrome of Osler-Weber-Rendu syndrome and juvenile polyposis and an unidentified HHT3 gene linked to chromosome 5.^[2]

Chromosome arm 9q33-34 (HHT1) harbors the endoglin gene, which encodes for a homodimeric integral membrane glycoprotein expressed at high levels on human vascular endothelial cells. Over 150 mutations of the endoglin gene have been reported in family members with Osler-Weber-Rendu syndrome. The vast majority of these mutations create premature stop codons and subsequently reduce levels of functional endoglin protein, the likely cause of Osler-Weber-Rendu syndrome type 1.

Chromosome arm 12q11-14 (HHT2) contains the activin receptorlike kinase 1 (ALK1), which encodes for a surface receptor for the transforming growth factor (TGF)–beta superfamily of ligands. The TGF-beta multifunctional protein plays an important role in angiogenesis and vascular remodeling. Over 120 mutations have been reported in the ALK1 gene; unlike Osler-Weber-Rendu type 1, more than 50% of the mutations contributing to type 2 are missense substitutions.

In patients with the HHT1 genotype, the prevalence of pulmonary and cerebral AVMs was shown to be higher than that of patients with the HHT2 genotype. Also, oral and nasal mucosal telangiectasias present earlier in life in patients with the HHT1 genotype. The prevalence of hepatic AVMs is higher in patients with HHT2 than in patients with HHT1. Patients with the HHT2 genotype also present earlier in life with dermal lesions.^[3]

United States statistics

Reported incidence is 1-2 cases per 100,000 population per year, with a prevalence of 1-2 cases per 10,000 population. The disease has a clinical penetrance of 97%.

International statistics

The worldwide prevalence is 1 case per 5,000-10,000 population, with a much higher incidence in the Danish island of Fyn, the Dutch Antilles, and parts of France.

Racial, sexual, and age-related differences in incidence

The disease most commonly occurs in whites, but it has been described in people of Asian, African, and Arabic descent. The syndrome occurs with equal frequency and severity in both sexes.

Most patients present by the third decade of life, but the disease may also be clinically silent. The most common presentation is recurrent epistaxis, which often develops prior to the second decade of life. AVMs may be congenital in nature, therefore they may present as early as the first year of life.

Prognosis greatly depends on the severity of the disease. Overall, Life expectancy appears to be significantly shorter in patients with Osler-Weber-Rendu syndrome^[4] ; nevertheless, with appropriate screening and aggressive management, life expectancy may approach that of the normal population.

Patients are at risk for hemorrhage from both mucosal and visceral sites, as well as high-output cardiac failure, cerebral abscess, ischemic stroke, migraines and further sequelae. Mortality rates show an early peak at age 50 years and a later peak at 60-79 years due to acute complications.

Recurrent epistaxis is observed in as many as 90% of patients. In one half of patients, the epistaxis becomes more serious with age, and blood transfusions are required in 10-30% of patients. Patients with pulmonary AVMs and telangiectasis of the GI tract are at risk for life-threatening hemorrhage of the lungs and GI tract.

Cerebral abscess due to impaired function of pulmonary vasculature is the most common neurologic manifestation of Osler-Weber-Rendu syndrome. Also, patients with this disease suffer from strokes, which may be either hemorrhagic or ischemic. Ischemic strokes likely due to pulmonary AVMs are common, whereas hemorrhagic strokes due to cerebral AVMs are far less common. Of patients who have pulmonary AVMs, 2% per year are estimated to have a stroke and 1% per year are estimated to develop a brain abscess.

Due to the presence of large AVMS and blood loss, high-output cardiac failure may occur. This known complication of HHT has been linked with the onset of severe and recurrent epistaxis in a small sample of patients.^[5]