Pediatric Care

Recommendations from the Second International HHT Guidelines (2020)

E1: The expert panel advises that diagnostic genetic testing be offered for asymptomatic children of a parent with HHT.

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Agreement
Quality of Evidence: High (Agreement 96%)

Two cross-sectional diagnostic studies demonstrated that genetic testing can identify subclinical or pre-symptomatic disease in children of HHT families with known mutation (77-79).


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Agreement

Strength of the Recommendation: Strong (Agreement 94%)


Clinical considerations: An affected family member should be tested first to determine the causative mutation, prior to testing an asymptomatic child who does not meet the clinical diagnostic criteria for HHT (Curaçao criteria)(4). The established clinical diagnostic criteria (Curaçao criteria)(4) for HHT are less reliable in young children, because many symptoms of HHT have onset in late childhood or even adulthood (age related penetrance)(168). It is generally accepted that for children to have pre-symptomatic testing for a genetic condition, there should be a clinical benefit to this testing. The value of this testing may be viewed differently depending on the specifics of the routinely recommended organ screening protocol in a given country for children with HHT. The alternatives, pros and cons should be discussed especially with younger patients or – as appropriate – their parents to achieve the best result for the patient.

E2: The expert panel recommends screening for pulmonary AVMs in asymptomatic children with HHT or at risk for HHT at the time of presentation / diagnosis.

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Agreement
Quality of Evidence: Moderate (Agreement 94%)

Several pediatric case series have demonstrated prevalence of pulmonary AVMs similar to adults and risk of life-threatening complications with good outcomes from embolization (80-85). Several series have reported two sensitive screening protocols in children(86-90) (Supplement Table 9).


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Agreement
Strength of Recommendation: Strong (Agreement 94%)

Clinical considerations: Screening may be performed with either chest X-ray and pulse oximetry OR transthoracic contrast echocardiography (TTCE). Screening with CT is not recommended, though CT chest remains the confirmatory diagnostic test when screening tests are positive.

E3: The expert panel recommends that large pulmonary AVMs and pulmonary AVMs associated with reduced oxygen saturation be treated in children to avoid serious complications.

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Agreement
Quality of Evidence: Moderate (Agreement 98%)

Case series demonstrated that children are at risk of serious complications from large pulmonary AVMs (or AVMs causing hypoxemia) (82, 83, 85), and embolization is safe and effective(85) (Supplement Table 10).


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Agreement
Strength of the Recommendation: Strong (Agreement 98%)

Clinical considerations: Pulmonary AVMs with feeding arteries ≥3 mm diameter are suitable for embolotherapy. Follow-up is indicated, to detect recanalization and reperfusion of treated AVMs and growth of small untreated AVMs. Specific protocols vary among centers (CT, oximetry or TTCE), as do intervals.

E4: The expert panel recommends repeating pulmonary AVM screening in asymptomatic children with HHT or at risk for HHT; typically at 5 year intervals.

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Agreement
Quality of Evidence: Low (Agreement 92%)

One case series demonstrated growth of pulmonary AVMs during childhood(91).


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Agreement

Strength of the Recommendation: Strong (Agreement 86%)


Clinical considerations: Typically, negative screening is repeated every 5 years. In children with indeterminate or borderline screening results, either based on imaging or oximetry, screening should be repeated sooner.

E5: The expert panel recommends screening for brain VM in asymptomatic children with HHT, or at risk for HHT, at the time of presentation / diagnosis.

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Agreement
Quality of Evidence: Low (Agreement 86%)

Case series demonstrated risk of intracranial hemorrhage from brain VMs(92-95) in children, MRI as sensitive screening test(96-98),  and benefits of surgical and endovascular management(99, 100), with also significant risk.


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Agreement

Strength of the Recommendation: Strong (Agreement 86%)


Clinical considerations: First-line screening is MRI (contrast enhanced more sensitive) to identify brain VM and determine subtype and risk factors for hemorrhage.  This typically requires sedation or anesthesia in young children. The decision to treat versus observe is based on risk of treatment versus risk of hemorrhage. As such, the decision to screen the child should be a shared decision among clinicians, caregivers and the child (where possible). There are important differences in clinical practice across countries: from screening asymptomatic children with MRI in infancy, to no routine screening of asymptomatic children for brain VM. Patient representatives felt strongly that children should be screened for brain VMs citing anecdotal evidence of disastrous outcomes in unscreened patients.

E6: The expert panel recommends that brain VMs with high risk features be treated.

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Agreement
Quality of Evidence: Low (Agreement 100%)

Case series demonstrated risk of intracranial hemorrhage from brain VMs(92-95),  identified high risk features(95, 101, 102) benefits of surgical and endovascular management(99, 100), with also significant risk.


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Agreement

Strength of the Recommendation: Strong (Agreement 98%)


Clinical considerations: Given the need to balance natural history risk with treatment risk, children with HHT who have brain VM should be referred to a center with multidisciplinary expertise in neurovascular disease management. Treated brain VMs require close follow-up; the follow-up for small (untreated) brain VMs is not well defined.

Background

The previous guidelines regarding diagnosis and management of HHT(5) focused on screening and treatment of adults. While some manifestations such as telangiectasia and epistaxis manifestations are age dependent and may be absent in young children with HHT, potentially serious and even life-threatening complications of visceral AVMs can occur at any age. Currently, the literature about diagnosis and management in children with HHT is limited, but protocols for screening and treatment of children with HHT have been developed in HHT centers around the world. Complications described in the literature are mostly due to pulmonary arteriovenous malformations (AVMs) and brain vascular malformations (VMs). Therefore, the focus of the pediatric HHT guidelines is on screening and management of pulmonary AVMs and brain VMs

Since establishing the diagnosis of HHT based on clinical criteria is less reliable in children than in adults(168), a different approach is required in this age group, with genetic testing playing a more important role than in adults(77-79). HHT is an autosomal dominant disease with age-related but high penetrance; therefore, every child of a parent with HHT has a 50% chance of inheriting the disease. Genetic testing in children is usually performed in a stepwise approach in which the affected parent is tested first (see overall Background section). If a pathogenic variant has been identified in the index case or in other affected member of the family(5), genetic testing can be used to establish the diagnosis in children prior to screening for visceral AVMs. Equally important, genetic testing can identify non-affected children who can be released from follow-up.

The prevalence of pulmonary AVMs varies with the type of HHT: pulmonary AVMs are found in about 50% of patients with HHT1 and in about 10% of patients with HHT2(120, 156). While these estimates are based on studies in adults, data suggest that the prevalence of pulmonary AVM is comparable in children(80-83). This is supported by one study that found a similar prevalence of pulmonary AVM in children with HHT1 as in their parents suggesting that the vast majority of pulmonary AVMs are present early in life(84). This has important implications for screening as the yield in genetically confirmed cases is high. Pulmonary AVMs are found in children with all types of HHT and at any age. Pulmonary AVMs associated with low oxygen saturations (< 96% at sea level), as well as large pulmonary AVMs, can cause serious, sometimes life-threatening complications, including hemorrhage, brain abscess and stroke(82, 83, 85). For that reason, screening children with HHT or at risk for HHT is indicated after birth, or at the time of presentation. Two screening protocols have been studied in children (Supplement Table 9); at present both are seen as equivalent. The first screening approach (“Dutch protocol”) uses a conservative screening strategy of oximetry and chest X-ray. As small pulmonary AVMs cannot be excluded in this setting, procedural antibiotic prophylaxis is recommended to all subjects. Evidence from the Dutch cohort suggests that this protocol is sufficient to prevent pulmonary AVM related complications(90). Transthoracic contrast echocardiography (TTCE) is used in the second screening protocol and has a higher sensitivity as a screening test for pulmonary AVMs(86, 87). It requires an intravenous access and has not clearly been shown to detect additional pulmonary AVMs that would cause complications in childhood. TTCE has the advantage of being a non-radiating test. The use of a quantitative scoring system for analysis of TTCE can increase the specificity of the test and can be used to determine whether a CT-scan should be performed(88), as the diagnostic confirmatory test(88, 169).

Embolotherapy of pulmonary AVMs has a high success rate in children(85) (Supplement Table 10). There are however no data to suggest that small pulmonary AVMs associated with normal oxygen saturation need to be treated in children. In rare cases, larger pulmonary AVMs with normal saturation can occur and treatment can be considered, especially in the case of symptoms. Growth of pulmonary AVMs over time has also been documented in children(91); therefore follow-up of children is important to capture these changes.

Brain VM is a general term that encompasses three principal types of vascular lesions in HHT: nidus brain AVM, brain arteriovenous fistula (AVF), and capillary vascular malformation (CVM)(170). These vascular malformations are thought to have significantly different natural history risk for spontaneous brain hemorrhage, ranging from extremely low in CVM, to intermediate in brain AVM (as can be further risk-stratified with detailed angio-architectural information, see CR6 below), to high in AVF. Overall, brain VM are less common than pulmonary AVMs in HHT. The prevalence in children is not well defined; data from studies in adults suggest that brain VMs are found in 8-16% of patients with HHT1 and 1-2% of patients with HHT2(171-173), though the AVF type appears to be over-represented in children(92, 174). Brain VMs can be present from birth and there are often no warning signs or symptoms prior to hemorrhage of a brain VM(175, 176). Clinical symptoms are subtle or absent in children and case series from different centers have described brain hemorrhage in children prior to diagnosis or screening procedures(93, 94, 175). The purpose of imaging screening of children with HHT is to identify if a brain VM is present and, to the extent possible, differentiate between the three common subtypes of brain VM. The most sensitive and specific non-invasive imaging modality to identify brain VM is MRI(96-98).

Observational studies suggest that treatment of brain VM is successful and can prevent brain hemorrhage(92, 100) (Supplement Table 10). Brain VM with relatively high natural history risk for rupture include pial AVFs as well as nidus brain AVMs with specific angio-architectural features or evidence of prior hemorrhage(95, 101, 102, 170, 177). High risk features for future nidus brain AVM rupture, sometimes identifiable on MRI but more reliably identified on digital subtraction angiography (DSA), include but are not limited to: feeding artery aneurysms, nidus aneurysms, venous outflow stenoses, and deep venous drainage. Intra-lesional microhemorrhage seen on brain MRI is an independent risk factor for future nidus brain AVM rupture(102).

It is important to appreciate that while the recommendations below are based on consensus of experts in the field, different approaches regarding pre-symptomatic genetic testing and screening procedures are used in different countries. Whenever possible, these different strategies are mentioned in the recommendations.

 

Second International Guidelines

Download 2019 HHT Guidelines 

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