Hereditary hemorrhagic telangiectasia (HHT) can be clinically diagnosed, but children often lack characteristic features. We report a family with homozygous growth differentiation factor 2 (GDF2)–related HHT diagnosed by genetic testing. A boy aged 5 years and 2 months presented with isolated hypoxemia. He was the product of a consanguineous marriage; his parents were second cousins. Physical examination revealed cyanosis of nail beds and clubbed fingers. Pulse oxygen saturation was 84% to 89%. Lung function, contrast-enhanced lung computed tomography, and noncontrast echocardiography were normal. A pulmonary perfusion scan revealed radioactivity in the brain and bilateral kidney, suggesting the existence of a intrapulmonary shunt. Whole-exome sequencing revealed a homozygous variant [c.1060_1062delinsAG (p.Tyr354ArgfsTer15)] in GDF2, which was found to be inherited from his heterozygous parents. At the age of 8 years, he developed epistaxis, and an angiogram revealed diffuse pulmonary arteriovenous malformations. At the age of 9 years, he was treated with sirolimus, and his condition improved significantly. However, his now 7-year-old sister with the same homozygous variant currently has no symptoms. Physical examinations revealed 1 pinpoint-sized telangiectasia on the chest of his mother and a vascular lesion on the forehead of his sister. Additionally, the patient’s father and great-uncle had a history of mild to moderate epistaxis. Mutation in GDF2 is a rare cause of HHT. Ours is the first report of homozygous GDF2-related HHT; in addition, this variant has not been reported previously. In our report, we also confirm variable expressivity, even with the same pathogenic variant in GDF2-related HHT.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disorder of blood vessel formation characterized by mucocutaneous and visceral vascular malformations resulting in direct communication between arterioles and venules.1  This process is thought to occur in a stepwise fashion, starting with dilation of postcapillary venules, followed by arteriolar dilation and then loss of the intervening capillary bed. Because of abnormal vascular development, patients with HHT tend to form abundant vascular networks between the veins and arteries, including telangiectasia, arteriovenous malformation (AVM) and arteriovenous fistula.2,3  These malformations lead to variable clinical manifestations, depending on where they occur and to what extent. One study revealed that 30% of children who were initially negative for pulmonary arteriovenous malformations (pAVMs) subsequently developed within 5 years.4  Thus, children with HHT require continued follow-up through adulthood.

HHT is diagnosed clinically by (1) recurrent epistaxis; (2) telangiectases of the lips, oral cavity, fingers, nasal mucosa, and gastrointestinal tract; (3) a family history of HHT; and (4) internal organ AVMs (particularly in the lungs, liver, and brain) according to the Curaçao criteria.1,5  The diagnosis is defined as “definite HHT” if ≥3 of these criteria are present and “possible HHT” if 2 criteria are present.5  Although HHT can be clinically diagnosed by using the Curaçao criteria, children often lack characteristic features such as telangiectasia68  or only have mild epistaxis.9  Because the symptoms of HHT are age-dependent, genetic testing for a pathogenic mutation is considered the gold standard in the pediatric population for patients with a family history of HHT.10  Genetic testing is the best way to determine definitively if a child with a family history of HHT has the condition, and genetic testing is also helpful if children have ≥1 symptoms of HHT. Because they may not yet meet criteria, when genetic test results are positive, it will confirm the diagnosis regardless of family history or symptoms.

In most cases, HHT is caused by a mutation in 1 of 2 genes: endoglin (HHT 1) or activin receptor-like kinase I/activin A receptor, type II-like kinase 1 (ALK1/ACVRL1) (HHT 2).11  A minor proportion of affected individuals have mutations in 2 additional loci that have not yet had a gene identified on chromosome 5q31 (HHT 3)12  or chromosome 7q14 (HHT 4),13  in the growth differentiation factor 2 (GDF2)/bone morphogenetic protein(BMP)9 gene (HHT 5)14  or in the SMAD family member 4 (SMAD4) gene (combined syndrome of juvenile polyposis and HHT, also associated with aortopathy).15  There have been reported differences between GDF2-related vascular-anomaly syndrome and HHT.14  To our knowledge, only 4 individuals with GDF2-related vascular-anomaly syndrome have been reported.14,16  All of these cases were heterozygous. The individuals presented with relatively infrequent and mild nosebleeds, and small blanching vascular lesions (larger than typical telangiectases) on the upper body and trunk rather than limited to the hands, face, and mouth (as is typical of HHT), so GDF2-related syndrome sometimes was reported as “similar” to HHT.14  A single case report identified a case of childhood-onset pulmonary artery hypertension harboring a homozygous GDF2 truncating mutation (p.Q26×),17  and recent studies have independently identified heterozygous GDF2 mutations in pulmonary artery hypertension cohorts.18  Additionally, RAS p21 protein activator (RASA)1 and ephrin receptor B4 (EPHB4) mutations cause capillary malformation–AVM, which also shows some overlap with HHT.16,19 

In this study, we report on a pediatric patient who presented with isolated hypoxemia.

A boy, aged 5 years and 2 months, presented with a 1-year history of decreased activity and cyanosis after exercise (82%–85% of pulse oxygen saturation [Spo2]). He was the product of a consanguineous marriage; his parents were second cousins (Fig 1). His family history revealed that his father had had a few episodes of mild epistaxis when he was a school-aged child, although he never required medical intervention. His mother and his sister (age 3) had never experienced nosebleeds. His paternal uncle had recurrent mild to moderate epistaxis into adulthood (Fig 1). Physical examinations (PEs) revealed only 1 pinpoint-sized telangiectasia on the right chest of his mother and no telangiectasias on him or his father (Fig 1). His sister had a dull purple vascular lesion (3 × 2 mm) on her forehead at birth that persisted into childhood, unlike the expected course for nevus simplex (Fig 2A). His sister had no additional cutaneous vascular lesions. His routine blood test revealed a red blood cell count of 5.36 × 1012/L and a hemoglobin (Hb) level of 15.5 g/dL, suggesting a mild polycythemia. The patient was initially suspected of having a hemoglobinopathy such as methemoglobinemia. Hb electrophoresis revealed no abnormalities. Sanger sequencing results of CYB5A and CYB5R3, associated with methemoglobinemia, were negative.

FIGURE 1

The family tree with male in □, female in ○, epistaxis in blue, and telangiectasias in brown is shown. P, proband.

FIGURE 1

The family tree with male in □, female in ○, epistaxis in blue, and telangiectasias in brown is shown. P, proband.

FIGURE 2

A, A vascular lesion (3 × 2 mm) on the left forehead of the sister of the proband. B–D, A bronchoscopy revealed slightly increased small blood vessels and bronchial submucosal spot hemorrhages localized to the wall of bronchus. E and F, A pulmonary perfusion scan revealed radioactivity in the bilateral kidney, suggesting the existence of a intrapulmonary shunt.

FIGURE 2

A, A vascular lesion (3 × 2 mm) on the left forehead of the sister of the proband. B–D, A bronchoscopy revealed slightly increased small blood vessels and bronchial submucosal spot hemorrhages localized to the wall of bronchus. E and F, A pulmonary perfusion scan revealed radioactivity in the bilateral kidney, suggesting the existence of a intrapulmonary shunt.

At initial presentation to the respiratory medicine clinic, a PE revealed a body weight of 19.5 kg, cyanosis of nail beds, and clubbed fingers. His BMI was 16.1. He had no obvious shortness of breath at rest. Blood count revealed a Hb level of 10.5 to 14.6 g/dL and a platelet count of 374 × 109/L. In laboratory investigations, we detected normal liver enzymes and renal function. Screening for metabolic diseases, contrast-enhanced (CE) lung computed tomography (CT) (slice thickness 1.25 mm) with vascular three-dimensional reconstruction, noncontrast echocardiography, abdominal ultrasonography, and abdominal CE-CT revealed no abnormalities. Additionally, CE-CT did not reveal aortic root dilation. Noncontrast MRI of the brain was performed, which revealed punctate myelinated dysplasia in the right frontal cortex, although he had no signs of neurologic abnormalities on examination. Noncontrast magnetic resonance angiography and magnetic resonance venography of the brain were normal. A bronchoscopy revealed slightly increased small blood vessels and submucosal spot hemorrhages, mainly localized to the wall of left main bronchus (Fig 2 B–D). Bronchoalveolar lavage fluid revealed a total cell count of 0.17 × 106/mL with 87% of macrophages, 11% of lymphocytes, and 2% of neutrophils. There was no evidence of hemosiderin-laden alveolar macrophages in the bronchoalveolar lavage fluid to suggest pulmonary hemorrhage.

The pressure of arterial oxygen was 47 to 60 mm Hg. Arterial blood oxygen saturation was 82% and 86% in standing and supine positions, respectively. Spo2 was 84% to 89%. Pulmonary function (PF) (impulse oscillometry system) was normal. We highly suspected he had a cardiopulmonary vascular malformation. Therefore, a pulmonary perfusion scan was performed and revealed radioactivity in the brain and bilateral kidney, suggesting the existence of intrapulmonary shunt due to pAVMs (Fig 2 E and F). Using trio whole-exome sequencing, we identified a homozygous variant [c.1060_1062delinsAG (p.Tyr354ArgfsTer15)] in GDF2 in our proband, which had been inherited from both of his heterozygous parents. The patient received treatment with intermittent low-flow supplemental oxygen and was lost to follow-up.

We ultimately diagnosed homozygous GDF2-related HHT in the patient and heterozygous GDF2-related HHT in his parents. Transthoracic contrast echocardiography was not performed during the initial hospitalization because the diagnosis of HHT was not considered until the genetic testing resulted, mainly because of our limited awareness of HHT at that time.

Three years later at the age of 8 years, he developed mild epistaxis (mainly dripping and lasting for ∼1 minute) occurring every 2 to 5 months, although he never required medical intervention. Transthoracic contrast echocardiography at that time was positive with Barzilai grade 3 (5 beats, a large number of microbubbles), and angiogram revealed diffuse pAVMs (distortion of diffuse pulmonary small arteries and capillary beds). Abdominal ultrasonography and abdominal CE-CT were normal. The following year at the age of 9, Spo2 was 79% to 82% (nasal cannula oxygen, fraction of inspire o2 90%–93%; flow of 2.0 L per minute), and he was no longer experiencing nosebleeds. He was more prone to fatigue, and he had difficulty walking to school (1 km). A PE revealed abundant vascular networks in his ears but no discrete cutaneous vascular malformations. No nasal telangiectasias were detected by the otolaryngologist. Noncontrast echocardiography was normal with no evidence of pulmonary hypertension. Conventional PF revealed small airway impairment with a 52.6% of forced expiratory flow 75. Lung diffusion capacity for carbon monoxide (DLCO) revealed moderate reduction (52.5%, normal range is 80%–120%). He started treatment with sirolimus (0.8 mg/m2 once daily orally) 4 months ago, at the age of 9 years. Spo2 increased to 87% on nasal cannula (fraction of inspire o2 of 90%–93%; flow of 2.0 L per minute), his physical strength improved significantly, and he could run after 14 days on treatment. However, Spo2 began to fall after 1 month on treatment. When Spo2 further decreased to 80%, sirolimus was discontinued after 3 months of treatment.

Sanger sequencing revealed the same homozygous variant in his now 7-year-old sister. Her conventional PF was normal, but DLCO revealed a mild reduction (61.5%). She and her parents do not currently have symptoms, and their Spo2 were 100% in sitting, standing, and lying positions. None of the 4 family members had any new skin findings at recent follow-up.

Vascular endothelial growth factor (VEGF) has been shown to be an important biomarker in HHT.20  Serum VEGF was elevated in HHT patients compared to control subjects.20  Importantly, it might be a potential predictive biomarker for therapeutic response in HHT.21  Therefore, serum VEGF levels were evaluated in this patient, in addition to endoglin. Results of serum endoglin and VEGF in the family members and control subjects are summarized in Table 1.

TABLE 1

Results of Serum Endoglin and VEGF in the Family Members

PatientAge, yEndoglin, ng/mLVEGF, pg/mL
Proband — — 
 Before treatment — 21.70 487.83 
 14 d after start of treatment with sirolimus — 24.06 267.65 
 40 d on treatment with sirolimus — 24.15 312.13 
Sister 26.31 381.64 
Mother 31 18.58 590.67 
Father 30 18.32 169.97 
Control 1 (normal, male) 55 21.26 219.5 
Control 2 (normal, male) 48 28.9 354.4 
Control 3 (normal, male) 20 24.8 112.1 
Control 4 (normal, female) 47 24.0 190.3 
Control 5 (PL, female) — — 
 Before treatment — 23.5 67.9 
 14 d after start of treatment with sirolimus — 24.0 112.0 
Control 6 (BP, male) 17.7 245.7 
Control 7 (ILD, male) 12.4 7.6 
Control 8 (SMPP-AO, male) 11.3 236.0 
Control 9 (SMPP, female) 11 15.7 391.7 
Control 10 (BP, male) 30.1 180.0 
Control 11 (ILD, male) 12.7 220.9 
Control 12 (SMPP, female) 12 21.6 416.6 
Control 13 (SMPP, male) 17.3 459.5 
PatientAge, yEndoglin, ng/mLVEGF, pg/mL
Proband — — 
 Before treatment — 21.70 487.83 
 14 d after start of treatment with sirolimus — 24.06 267.65 
 40 d on treatment with sirolimus — 24.15 312.13 
Sister 26.31 381.64 
Mother 31 18.58 590.67 
Father 30 18.32 169.97 
Control 1 (normal, male) 55 21.26 219.5 
Control 2 (normal, male) 48 28.9 354.4 
Control 3 (normal, male) 20 24.8 112.1 
Control 4 (normal, female) 47 24.0 190.3 
Control 5 (PL, female) — — 
 Before treatment — 23.5 67.9 
 14 d after start of treatment with sirolimus — 24.0 112.0 
Control 6 (BP, male) 17.7 245.7 
Control 7 (ILD, male) 12.4 7.6 
Control 8 (SMPP-AO, male) 11.3 236.0 
Control 9 (SMPP, female) 11 15.7 391.7 
Control 10 (BP, male) 30.1 180.0 
Control 11 (ILD, male) 12.7 220.9 
Control 12 (SMPP, female) 12 21.6 416.6 
Control 13 (SMPP, male) 17.3 459.5 

Endoglin (446507; Hangzhou Lianke Biology Co, Ltd, Zhejiang, China); VEGF (46507; Biolegend, San Diego, CA). AO, airway obliterans; BP, bacteria pneumonia; ILD, interstitial lung disease; PL, pulmonary lymphangioma; SMPP, severe mycoplasma pneumoniae pneumonia; —, not applicable.

The proband and his sister were confirmed to have rare homozygous GDF2-related HHT, and their parents were confirmed to have heterozygous GDF2-related HHT by genetic testing. The GDF2 p.Tyr354ArgfsTer15 is a likely pathogenic variant according to the American College of Medical Genetics standards and guidelines,22  because the mutation is predicted to result in loss of function. Pathogenicity is further supported by its absence in Exome Aggregation Consortium (ExAC), “1000G,” and Genome Aggregation Database (gnomAD). GDF2 binds with high affinity to ALK1 and endoglin, thereby activating downstream SMAD1/SMAD5 via the transforming growth factor-β (TGF-β) signaling pathway, which may regulate angiogenesis.2325  The amino acid residues Ser24 and Arg78 of GDF2 are the shared conserved binding sites of all TGF-β ligands, and Lys64 is the core binding site of the GDF2-ALK1 complex,26  so in theory, the truncated GDF2 protein chain resulting from p.Tyr354ArgfsTer15 may not affect the GDF2-mediated TGF-β signaling pathway. GDF2 binds to endoglin mainly through amino acid 402-416 of the protein chain,27  suggesting that the truncation of GDF2 in this region will result in inactivation of the endoglin-GDF2 signaling pathway rather than the TGF-β pathway. Several cases of GDF2-related syndrome may have provided clues to the GDF2 polypeptide chain required to maintain the GDF2-ALK1 complex function that the pathogenic mutations of GDF2 mainly occurred in the other 2 core binding regions of the GDF2-ALK1 complex, that is, Pro85 and Arg68, demonstrated by Wooderchak-Donahue et al.14  Additionally, the missense mutation at Arg333 mainly affects the synthesis and maturation of the GDF2 protein, resulting in its decreased activity.14  In our cases, the pathogenic mutations of GDF2 revealed a dose effect. The GDF2 protein shortened by mutation, Tyr354ArgfsTer15, may not affect the activation of the TGF-β signaling pathway regulated by GDF2-ALK1, but the loss of endoglin-binding region, that is, amino acid 402–416, would result in complete loss of endoglin-GDF2 complex function, which might be the potential mechanism of atypical HHT and the cause of the mild HHT phenotype in some family members. We predict that heterozygous individuals have a milder phenotype than homozygous individuals because of the dosage effect (50% versus presumed 0% loss of function of GDF2). In examining the family tree, we identified only 4 other affected relatives, which did not reveal a rigorous cosegregation because the mother and the sister do not have epistaxis or other visible signs of HHT, and it implies that low penetration or variable expressivity may occur. Given that only 3 family members presented with mild or moderate epistaxis (epistaxis severity score of 0–3), it also suggests that the gene dosage effect may play a role in our cases with atypical HHT, which may be attributed to the specific GDF2 mutation.

Both our patient and his sister are homozygous for the GDF2 gene variation inherited from their heterozygous parents. The parents are second cousins, so we speculate that the mutation was passed in heterozygous form from one of their great-grandparents, through their grandmothers and mothers. The proband had a homozygous mutation exhibiting more severe clinical symptoms at an earlier age than previous family members. We predict that heterozygous individuals may have only mild or even no symptoms, whereas the homozygous individual has more severe symptoms because of complete loss of GDF2 function. However, his homozygous sister remains asymptomatic at the age of 7 years, which suggests variability in penetrance and severity of phenotype despite shared genotype. His sister might develop more symptoms with time, and we have not performed a bubble echo to determine if she has any intrapulmonary shunt that is not yet causing an issue with oxygen saturation. Although her conventional PF was normal, DLCO revealed mild reduction, suggesting injury of pulmonary capillary endothelial cells.

Our patient and his family members did not meet clinical criteria for HHT and were therefore difficult to diagnose with HHT. However, hypoxemia (clubbing, polycythemia) suggested possible pAVMs, which is highly associated with HHT. The parents declined the recommended screening outlined by the international HHT guidelines1  for themselves, their daughter, and their mothers because they believe that they and their heterozygous family members are healthy, including their sister grandmothers at 80 years of age. They have had few nosebleeds (present in only 3 family members) and no classic skin lesions. The location and relatively large size of the vascular lesion in the proband’s sister are not typical for those described in classic HHT (caused by endoglin and ACVRL1) but are consistent with previous reports of atypical lesions in GDF2-related HHT.

Some studies reveal that HHT can be misdiagnosed as asthma or other diseases, because of the subclinical presentation (such as failure to thrive and/or mild cough) at the time of investigation.7,28  In addition, many of the symptoms of HHT are age-related. Most patients report the appearance of telangiectases during the third decade.29  In HHT, AVMs typically occur in pulmonary, not bronchial, vasculature. However, in our present study, bronchoscopy revealed slightly increased small blood vessels and submucosal spot (nonpinpoint) hemorrhages primarily localized to the wall of left main bronchus, suggesting an increased pressure in the pulmonary and bronchial circulation, and suspicious for bronchial vascular malformation. To our knowledge, only 1 patient has been reported to have telangiectases of the bronchial mucosa.30 

The prevalence of pAVMs is higher in endoglin-related HHT than in ALK1-related HHT.28  pAVMs may be asymptomatic; present as respiratory symptoms of hemoptysis, dyspnea, hypoxemia or digital clubbing; or present with neurologic symptoms because of paradoxical emboli including stroke, transient ischemic attacks, or unusual infections, including brain abscesses.7,28  In the first hospitalization of our proband, Spo2 was as low as 82% to 85%, suggesting a pAVM of such size that it should have been detected on chest CT. In the absence of visible large pAVM, we speculated that there were multiple small or even diffuse pAVMs. Although brain MRI revealed no evidence of AVMs, it did reveal multiple punctate lesions consistent with previous paradoxical emboli through pAVMs.

HHT is a progressive vascular disease with potential mortality. Although there is no cure for HHT, there are treatments for the symptoms of HHT. Targeted anti-angiogenic therapies have shown great promise including bevacizumab and pazopanib.3133  Bevacizumab, an anti-VEGF antibody, is a rational therapeutic for HHT because it may reduce excessive angiogenesis, which can improve quality of life, decreasing nasal and/or gastrointestinal bleeding.31,32  Unfortunately, bevacizumab is not available at our hospital. Pazopanib may reduce bleeding in HHT,33  but has not yet become available in China. Oral low-dose tacrolimus improved ALK1-HHT-associated epistaxis in one study.34  Recent studies have revealed that PI3K-Akt signaling is overactivated in several HHT models and that its inhibition reduces the AVMs.35  Our proband ultimately started treatment with sirolimus. His symptoms improved, and the concentration of serum VEGF decreased within 1 month. Subsequently, however, his Spo2 started to decrease, and the concentration of serum VEGF increased, so sirolimus was discontinued after 3 months of treatment. One recent study revealed that combined correction of endothelial Smad1/5/8, mammalian target of rapamycin (mTOR), and VEGF receptor 2 (VEGFR2) pathways opposes HHT pathogenesis36  and may explain our treatment failure of sirolimus alone. Repurposing of sirolimus (mTOR inhibitor) in conjunction with a VEGF inhibitor such as nintedanib might provide therapeutic benefit in HHT patients.36  As shown in Table 1, VEGF might not completely be associated with disease severity, and it may increase in mycoplasma pneumoniae pneumonia patients37  and other control individuals, but it may be used to dynamically assess treatment response. Serum endoglin was normal in the family, and it could help to exclude HHT caused by endoglin defects. However, further functional studies should be conducted to confirm these mechanismal hypotheses.

There are few published reports of patients with GDF2 mutations to date and none with our present mutation.9,11  In addition, the homozygous state has never been reported, constituting an important new finding for researchers and clinicians studying HHT.

HHT can be clinically diagnosed by using the Curaçao criteria, but children often lack characteristic features. HHT should be considered in the differential diagnosis of hypoxemia, even isolated hypoxemia. GDF2 mutations can be homozygous whereas other HHT-related genes have not been reported in the homozygous state. GDF2-related HHT reveals variability in phenotype among affected individuals, which may be due in part to, but is not completely explained by, gene dosage.

We thank Ke Xu, Xiaofang Quan, and other staff at Beijing Chigene Translational Medicine Research Center for their expert technical assistance. We thank Xiaoyan Zhang (Capital Medical University) for performing the enzyme-linked immunosorbent assay experiment and Yixin Ren and Nannan Jiang (Department of Pulmonary Function at Beijing Children’s Hospital) for performing lung function for the children. We thank Dr Hui Xu and the nurses in our department and Xin Zhang in the heart center at Beijing Children’s Hospital for their cooperation. We thank the patient and his family for their kind cooperation. We also thank the reviewers for their substantial revision of this article.

Dr Liu supervised the patient care, conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Yang performed the lung scintigraphy, designed the study, and reviewed and revised the manuscript; Drs Tang, Li, and Shen supervised the patient care, designed the study, collected data, and reviewed and revised the manuscript; Dr Gu performed genetic analysis, designed the study, collected data, and reviewed and revised the manuscript; Dr Zhao conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: Supported by Beijing Municipal and Commission Health and Family Planning (2015-3-076) and The National Key Research and Development Program of China (2016YFC0901502).

     
  • ALK1

    activin receptorlike kinase I

  •  
  • AVM

    arteriovenous malformation

  •  
  • CE

    contrast-enhanced

  •  
  • CT

    computed tomography

  •  
  • DLCO

    lung diffusion capacity for carbon monoxide

  •  
  • GDF2

    growth differentiation factor 2

  •  
  • Hb

    hemoglobin

  •  
  • HHT

    hereditary hemorrhagic telangiectasia

  •  
  • pAVM

    pulmonary arteriovenous malformation

  •  
  • PE

    physical examination

  •  
  • PF

    pulmonary function

  •  
  • Spo2

    pulse oxygen saturation

  •  
  • TGF-β

    transforming growth factor-β

  •  
  • VEGF

    vascular endothelial growth factor

1
Faughnan
ME
,
Palda
VA
,
Garcia-Tsao
G
, et al;
Hereditary Hemorrhagic Telangiectasia Foundation International - Guidelines Working Group
.
International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia
.
J Med Genet
.
2011
;
48
(
2
):
73
87
2
Kodati
R
,
Prasad
KT
.
Arteriovenous malformations in multiple organs in a patient presenting with hereditary haemorrhagic telangiectasia
.
BMJ Case Rep
.
2019
;
12
(
5
):
e230441
3
Zhang
D
,
Zhou
F
,
Zhao
X
,
Liu
B
,
Chen
J
,
Yang
J
.
Endoglin is a conserved regulator of vasculogenesis in zebrafish - implications for hereditary haemorrhagic telangiectasia
.
Biosci Rep
.
2019
;
39
(
5
):
BSR20182320
4
Mowers
KL
,
Sekarski
L
,
White
AJ
,
Grady
RM
.
Pulmonary arteriovenous malformations in children with hereditary hemorrhagic telangiectasia: a longitudinal study
.
Pulm Circ
.
2018
;
8
(
3
):
2045894018786696
5
Shovlin
CL
,
Guttmacher
AE
,
Buscarini
E
, et al
.
Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)
.
Am J Med Genet
.
2000
;
91
(
1
):
66
67
6
Fernandopulle
N
,
Mertens
L
,
Klingel
M
,
Manson
D
,
Ratjen
F
.
Echocardiography grading for pulmonary arteriovenous malformation screening in children with hereditary hemorrhagic telangiectasia
.
J Pediatr
.
2018
;
195
:
288
291
7
Gefen
AM
,
White
AJ
.
Asymptomatic pulmonary arteriovenous malformations in children with hereditary hemorrhagic telangiectasia
.
Pediatr Pulmonol
.
2017
;
52
(
9
):
1194
1197
8
Gonzalez
CD
,
Cipriano
SD
,
Topham
CA
, et al
.
Localization and age distribution of telangiectases in children and adolescents with hereditary hemorrhagic telangiectasia: a retrospective cohort study
.
J Am Acad Dermatol
.
2019
;
81
(
4
):
950
955
9
Gonzalez
CD
,
Mcdonald
J
,
Stevenson
DA
, et al
.
Epistaxis in children and adolescents with hereditary hemorrhagic telangiectasia
.
Laryngoscope
.
2018
;
128
(
7
):
1714
1719
10
Pahl
KS
,
Choudhury
A
,
Wusik
K
, et al
.
Applicability of the Curaçao criteria for the diagnosis of hereditary hemorrhagic telangiectasia in the pediatric population
.
J Pediatr
.
2018
;
197
:
207
213
11
McAllister
KA
,
Grogg
KM
,
Johnson
DW
, et al
.
Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1
.
Nat Genet
.
1994
;
8
(
4
):
345
351
12
Cole
SG
,
Begbie
ME
,
Wallace
GMF
,
Shovlin
CL
.
A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5
.
J Med Genet
.
2005
;
42
(
7
):
577
582
13
Bayrak-Toydemir
P
,
McDonald
J
,
Akarsu
N
, et al
.
A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7
.
Am J Med Genet A
.
2006
;
140
(
20
):
2155
2162
14
Wooderchak-Donahue
WL
,
McDonald
J
,
O’Fallon
B
, et al
.
BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia
.
Am J Hum Genet
.
2013
;
93
(
3
):
530
537
15
Andrabi
S
,
Bekheirnia
MR
,
Robbins-Furman
P
,
Lewis
RA
,
Prior
TW
,
Potocki
L
.
SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction
.
Am J Med Genet A
.
2011
;
155A
(
5
):
1165
1169
16
Hernandez
F
,
Huether
R
,
Carter
L
, et al
.
Mutations in RASA1 and GDF2 identified in patients with clinical features of hereditary hemorrhagic telangiectasia
.
Hum Genome Var
.
2015
;
2
:
15040
17
Wang
G
,
Fan
R
,
Ji
R
, et al
.
Novel homozygous BMP9 nonsense mutation causes pulmonary arterial hypertension: a case report
.
BMC Pulm Med
.
2016
;
16
:
17
18
Wang
X-J
,
Lian
T-Y
,
Jiang
X
, et al
.
Germline BMP9 mutation causes idiopathic pulmonary arterial hypertension
.
Eur Respir J
.
2019
;
53
(
3
):
1801609
19
Amyere
M
,
Revencu
N
,
Helaers
R
, et al
.
Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling
.
Circulation
.
2017
;
136
(
11
):
1037
1048
20
Botella
L-M
,
Albiñana
V
,
Ojeda-Fernandez
L
,
Recio-Poveda
L
,
Bernabéu
C
.
Research on potential biomarkers in hereditary hemorrhagic telangiectasia
.
Front Genet
.
2015
;
6
:
115
21
Liu
DT
,
Frohne
A
,
Koenighofer
M
, et al
.
Plasma VEGF - a candidate biomarker for response to treatment with bevacizumab in HHT patients
.
Rhinology
.
2020
;
58
(
1
):
18
24
22
Richards
S
,
Aziz
N
,
Bale
S
, et al;
American College of Medical Genetics and Genomics Laboratory Quality Assurance Committee
.
Standards and Guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
.
Genet Med
.
2015
;
17
(
5
):
405
424
23
Scharpfenecker
M
,
van Dinther
M
,
Liu
Z
, et al
.
BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis
.
J Cell Sci
.
2007
;
120
(
pt 6
):
964
972
24
Bidart
M
,
Ricard
N
,
Levet
S
, et al
.
BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain. [published correction appears in Cell Mol Life Sci. 2012;69(3):485]
.
Cell Mol Life Sci
.
2012
;
69
(
2
):
313
324
25
Kienast
Y
,
Jucknischke
U
,
Scheiblich
S
, et al
.
Rapid activation of bone morphogenic protein 9 by receptor-mediated displacement of pro-domains
.
J Biol Chem
.
2016
;
291
(
7
):
3395
3410
26
Townson
SA
,
Martinez-Hackert
E
,
Greppi
C
, et al
.
Specificity and structure of a high affinity activin receptor-like kinase 1 (ALK1) signaling complex
.
J Biol Chem
.
2012
;
287
(
33
):
27313
27325
27
Saito
T
,
Bokhove
M
,
Croci
R
, et al
.
Structural basis of the human endoglin-BMP9 interaction: insights into BMP signaling and HHT1
.
Cell Rep
.
2017
;
19
(
9
):
1917
1928
28
Aagaard
KS
,
Kjeldsen
AD
,
Tørring
PM
,
Green
A
.
Comorbidity among HHT patients and their controls in a 20 years follow-up period
.
Orphanet J Rare Dis
.
2018
;
13
(
1
):
223
29
Wooderchak-Donahue
WL
,
Akay
G
,
Whitehead
K
, et al
.
Phenotype of CM-AVM2 caused by variants in EPHB4: how much overlap with hereditary hemorrhagic telangiectasia (HHT)?
Genet Med
.
2019
;
21
(
9
):
2007
2014
30
Grudeva-Popova
JG
,
Vakrilov
VA
,
Karnolski
IN
.
Pulmonary, gastrointestinal and liver vascular malformations in Rendu-Osler disease
.
Folia Med (Plovdiv)
.
2000
;
42
(
3
):
60
63
31
Al-Samkari
H
.
Systemic bevacizumab for hereditary hemorrhagic telangiectasia: considerations from observational studies
.
Otolaryngol Head Neck Surg
.
2019
;
160
(
2
):
368
32
Al-Samkari
H
,
Kritharis
A
,
Rodriguez-Lopez
JM
,
Kuter
DJ
.
Systemic bevacizumab for the treatment of chronic bleeding in hereditary haemorrhagic telangiectasia
.
J Intern Med
.
2019
;
285
(
2
):
223
231
33
Faughnan
ME
,
Gossage
JR
,
Chakinala
MM
, et al
.
Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia
.
Angiogenesis
.
2019
;
22
(
1
):
145
155
34
Sommer
N
,
Droege
F
,
Gamen
KE
, et al
.
Treatment with low-dose tacrolimus inhibits bleeding complications in a patient with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension
.
Pulm Circ
.
2019
;
9
(
2
):
2045894018805406
35
Ola
R
,
Dubrac
A
,
Han
J
, et al
.
PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia
.
Nat Commun
.
2016
;
7
:
13650
36
Ruiz
S
,
Zhao
H
,
Chandakkar
P
, et al
.
Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models
.
J Clin Invest
.
2020
;
130
(
2
):
942
957
37
Jeong
Y-C
,
Yeo
M-S
,
Kim
J-H
,
Lee
H-B
,
Oh
J-W
.
Mycoplasma pneumoniae infection affects the serum levels of vascular endothelial growth factor and interleukin-5 in atopic children
.
Allergy Asthma Immunol Res
.
2012
;
4
(
2
):
92
97

Competing Interests

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