Educational aims
The reader will come to appreciate:
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HHT is an underdiagnosed condition, with a vast range of clinical manifestations.
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Pulmonary hypertension is a rare, but important complication of HHT.
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International guidelines recommend repeated screening for pulmonary and cerebral AVMs in children with HHT.
Abstract
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant condition characterised by small telangiectasias and larger multisystem arteriovenous malformations (AVMs). Common sites of AVMs include in the nose, lungs, brain and liver. These lesions are prone to rupture, leading to complications including recurrent epistaxis and significant haemorrhage. Pulmonary hypertension (PH) can also occur. This review presents an update on the genetics, clinical manifestations, management options, and screening recommendations for children with HHT.
Introduction
HHT, formerly known as Osler-Weber-Rendu syndrome, was first described in 1896 . It is an inherited multisystem vascular dysplasia, that results in telangiectasias and visceral AVMs . It is a genetically heterogenous disorder, with a number of genetic mutations implicated, leading to a varied phenotype. Whilst the prevalence has been estimated as 1 in 5000–6000 , HHT is often underdiagnosed due its wide range of clinical manifestations, which tend to increase with age.
Genetics
HHT is an autosomal dominant condition, resulting from loss of function mutations in protein-encoding genes within the transforming growth factor beta (TGFβ) signalling pathway . The TGFβ pathway is known to play an essential role in maintaining vascular integrity , modulating angiogenesis and vascular remodelling . Of relevance to HHT, endoglin and activin receptor like kinase (ALK1) are components of the TGFβ complex, predominantly expressed in endothelial cells , while SMAD4 is a critical downstream transcription factor . Interruptions along this pathway prevents appropriate signalling, resulting in disrupted angiogenesis, disorganised cytoskeletons and dysfunctional remodelling of the vascular endothelium . The result is dilated blood vessels known as telangiectasias and AVMs. In addition to vascular remodelling, endoglin is also speculated to have a role in the inflammatory process .
The majority (95 %) of patients carry mutations in ENG or ACVRL1 (Activin A receptor-like type I) . Table 1 lists genetic mutations commonly associated with HHT. ENG was first identified in 1994, and encodes for endoglin . ENG mutations are more commonly associated with pulmonary and cerebral AVMs . Whilst the majority of literature is based on adult studies, a recent large paediatric study confirmed this association in children .
| HHT | Gene | Chromosome | Protein |
|---|---|---|---|
| HHT 1 | ENG | 9q34.11 | Endoglin |
| HHT 2 | ACVRL1 | 12q13.13 | ALK1 |
| HHT-juvenile polyposis | SMAD4 | 18q21.2 | MADH4 |
ACVRL1 was first identified in 1996 , and encodes for ALK1. ACVRL1 mutations are more commonly associated with hepatic AVMs and pulmonary hypertension . Approximately 2 % of patients carry mutations in the SMAD4 gene, that encodes for the MADH4 (mothers against decapentaplegic homolog 4) protein . SMAD4 mutations are associated with gastrointestinal AVMs . More recently, the GDF2 gene has also been implicated in a small number of cases, however specific phenotypic associations are yet to be determined .
Diagnosis
The diagnosis of HHT can be confirmed by genetic testing or by the Curacao clinical criteria . Diagnosis using the Curacao clinical criteria is suggested if the patient has 3 out of 4 of the following criteria: spontaneous recurrent epistaxis, multiple mucocutaneous telangiectasias, visceral lesions, and a first-degree relative with HHT . Nonetheless, HHT may still be suspected when only 2 of the 4 criteria are met . However, it is important to note that the clinical criteria based diagnosis has a poor negative predictive value, particularly in paediatrics .
Clinical manifestations and management
Epistaxis
The most common and generally earliest manifestation of HHT is spontaneous recurrent epistaxis , affecting up to 96 % of patients . Epistaxis is usually present by the second decade of life . They may occur daily and can lead to significant iron deficiency anaemia . Management typically includes preventative measures, such as emollients and avoiding anticoagulants, while some may require topical decongestant sprays, nasal cauterisation, or oral tranexamic acid .
Telangiectasia
The majority of patients will also develop mucocutaneous telangiectasias , which appear as dilated or broken blood vessels near the surface of the skin or mucosa. They are usually present by the third decade of life . Characteristic sites of telangiectasias include lips, oral cavity, gastrointestinal tract (GIT), fingers, and nose . Telangiectasias tend to increase in number with age, leading to increased frequency of GIT bleeds .
Arterio-venous malformations
AVMs are common in HHT. They refer to direct communications between arteries with their draining veins, whereby abnormal vessels replace the usual capillary bed. They can be present in a number of visceral organs, including lungs, liver and brain . AVMs are prone to rupture, leading to urgent and at times life-threatening presentations with haemorrhage .
Pulmonary arterio-venous malformations
It is estimated that 15–50 % of patients with HHT have pulmonary AVMs . Pulmonary AVMs can be classified according to the artery involved; simple (1 feeding artery), complex (multiple feeding arteries), and diffuse (multiple small AVMs) . A fourth, recently described, pulmonary AVM is proposed as the telangiectatic, visible as a ground-glass lesion on CT .
Although pulmonary AVMs may be asymptomatic, they can also present with hypoxia secondary to shunting and haemoptysis secondary to haemorrhage . The risk of haemorrhage is higher in adults compared to children, with a particular increase observed in pregnancy . Multiple or recurrent pulmonary AVMs may continue to be a source of haemoptysis, leading to anaemia and cardiac strain . They may also present with neurologic complications, such as migraines, brain abscesses, embolic strokes and transient ischaemic attacks . These complications occur due to the bypassing of pulmonary capillary beds, which usually filters small thrombi and bacteria, allowing emboli to pass . For this reason, patients with pulmonary AVMs are recommended to have antibiotic prophylaxis for any procedure that carries risk of bacteraemia, including dental procedures .
Investigations typically include bubble echocardiography and CT chest with intravenous contrast, while recent studies have also shown efficacy for ultra-low dose CT in pulmonary AVMs > 2.5 mm .
The decision to treat pulmonary AVMs is based on the patient’s symptoms, impact on activities, risks of the intervention, as well as the risks of leaving the AVM untreated. International guidelines recommend treatment of large AVMs (>3 mm) associated with hypoxia to avoid or mitigate complications . Currently, the management typically involves a transcatheter approach to embolise the vessels with coils or plugs. There is evidence that embolisation reduces the shunt fraction and cardiac output . The improved oxygenation is due to the reduction in ventilation perfusion mismatch which results in pulmonary vasodilation . Fig. 1 depicts two pulmonary AVMs pre-embolisation compared with the appearance post-embolisation. Historically, surgical resection of the pulmonary AVMs, such as partial or total lobectomy, and pneumonectomy, was considered a therapeutic option but, with advances in catheter procedure technology, this is currently rarely utilised. Lung transplantation is reserved for those refractory to treatment .
Prior to the era of embolisation, the reported incidence of paradoxical stroke and cerebral abscess was as high as 30 % of patients with HHT and pulmonary AVM . The long-term success of embolisation has been reported to be 75 % . However, there remains a risk of recurrence in some, due to the development of collateral vessels and angiogenesis . For this reason, it is generally recommended to undergo a CT chest with contrast 3–6 months following embolisation .
Hepatic arterio-venous malformations
A small case series of children with HHT found hepatic AVMs in 47 % . They are classified as either vascular tumours (haemangiomas) or vascular malformations with altered flow . Hepatic AVMs are usually clinically silent in adults; however, some patients may present with reduced exercise tolerance, dyspnoea, oedema and ascites. This is due to the associated complications; high output cardiac failure, portal hypertension, hepatic encephalopathy and biliary disease . Cases of symptomatic hepatic AVMs in children are very rare .
Hepatic AVMs can be diagnosed on doppler ultrasound. Embolisation is typically avoided in this cohort as it is thought to be merely a temporising measure . Intravenous bevacizumab can be used in those with symptomatic high-output cardiac failure. Liver transplant can also be considered for those refractory to medical management .
Cerebral arterio-venous malformations
Cerebrovascular malformations are estimated to affect 10 % of people with HHT , and are more common in patients with an ENG mutation . These vary between patients, but may manifest as arteriovenous malformations, arteriovenous fistulas (AVF), capillary telangiectasias, cavernous malformations, and intracranial aneurysms . Those with large AVMs and aneurysms are at risk of rupture, with an estimated yearly rate of rupture of 1–2 % . AVMs are divided into 2 categories: nidal and AVF (non-nidal). Nidal AVMs consist of a tangle (nidus) of vascular connections between cerebral arteries and veins . There are rarely seen in early childhood, but not seen in neonates . AVFs refer to high flow AVMs consisting of direct communications between cerebral arteries and veins and can be present in neonates . Due to the lack of a nidus, AVFs pose a high risk of haemorrhage, and are thought to be the reason that cerebral haemorrhage is more common in children compared to adults with HHT . In comparison to adults, children are more likely to present with complications from their cerebral AVMs, such as intracranial haemorrhage and seizures . Capillary malformations and developmental venous anomalies are considered benign lesions, while cavernous lesions are non-shunting and low-pressure, with a very low rate of haemorrhage .
Management options for cerebral AVMs include embolisation, surgical resection, or radiosurgery, although these procedures carry significant risk of complications . For those at low risk of haemorrhage, a conservative approach is typically preferred .
Pulmonary hypertension
While the true prevalence of pulmonary hypertension (PH) in patients with HHT is uncertain, it is estimated to be present in 8–40 % . PH was first described as a complication of HHT by Sapru and colleagues in 1969 , and is associated with increased morbidity and mortality . The age of presentation with HHT associated PH is dependent on the underlying aetiology, with patients having high output heart failure presenting at a younger age. The emerging genotype-phenotype correlations have enabled a renewed focus upon screening and management of pH complicating HHT across the lifespan.
Diagnosis
The clinical presentation of pH ranges from being asymptomatic to progressive exertional dyspnoea. Symptoms described in adults, such as chest pain, are less common in children. PH is defined by a mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg that is ascertained by right heart catheterisation. Associated invasive findings of pH may include ECG changes of right atrial enlargement and right ventricular strain. Additionally, radiological changes of right heart and pulmonary artery enlargement may be visible on a plain chest x-ray. Echocardiography may reveal elevated tricuspid regurgitation velocity with associated right ventricular dilatation and septal flattening. Right ventricular systolic pressure (RVSP) may be estimated during echocardiogram assessment . Screening studies using RVSP during echocardiography have demonstrated a prevalence of pH ranging between 20 % and 31 % . The mean RVSP was demonstrated to be 73 mmHg (SD 17).
Right heart catheterisation is needed for the diagnosis and classification of PH. Precapillary PH is defined by a mPAP≥25 mmHg, pulmonary artery wedge pressure (PAWP) < 15 mmHg and pulmonary vascular resistance (PVR) > 2 Wood units. Post capillary PH is defined by a mPAP≥25 mmHg, PAWP>15 mmHg and PVR<2 Wood units. Combined pre and post capillary PH is defined by mPAP≥25 mmHg, PAWP>15 mmHg and PVR>2 Wood units .
PH may be classified into 5 clinical classes based on pathophysiology [ Table 2 ].
