Homozygous GDF2-Related Hereditary Hemorrhagic Telangiectasia in a Chinese Family Jinrong Liu, MD,a Jigang Yang, MD,b Xiaolei Tang, MD,a Huimin Li, MD,a Yuelin Shen, MD,a Weiyue Gu, PhD,c Shunying Zhao, MDa

Hereditary hemorrhagic telangiectasia (HHT) can be clinically diagnosed, but abstract 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 aDepartment of Respiratory Medicine, Beijing Children’s Hospital, National Center for Children’s Health and Capital hypoxemia. He was the product of a consanguineous marriage; his parents Medical University, Xicheng District, Beijing, People’s were second cousins. Physical examination revealed cyanosis of nail beds and Republic of China; bDepartment of Nuclear Medicine, Beijing clubbed fingers. Pulse oxygen saturation was 84% to 89%. Lung function, Friendship Hospital and Capital Medical University, Xicheng District, Beijing, People’s Republic of China; and cData and contrast-enhanced lung computed tomography, and noncontrast Analysis Center for Genetic Diseases, Beijing Chigene echocardiography were normal. A pulmonary perfusion scan revealed Translational Medicine Research Center Co, Ltd, Tongzhou District, Beijing, People’s Republic of China radioactivity in the brain and bilateral kidney, suggesting the existence of a intrapulmonary shunt. Whole-exome sequencing revealed a homozygous Dr Liu supervised the patient care, conceptualized GDF2 and designed the study, drafted the initial variant [c.1060_1062delinsAG (p.Tyr354ArgfsTer15)] in , which was manuscript, and reviewed and revised the found to be inherited from his heterozygous parents. At the age of 8 years, he manuscript; Dr Yang performed the lung developed epistaxis, and an angiogram revealed diffuse pulmonary scintigraphy, designed the study, and reviewed and revised the manuscript; Drs Tang, Li, and Shen arteriovenous malformations. At the age of 9 years, he was treated with supervised the patient care, designed the study, sirolimus, and his condition improved significantly. However, his now 7-year- collected data, and reviewed and revised the old sister with the same homozygous variant currently has no symptoms. manuscript; Dr Gu performed genetic analysis, Physical examinations revealed 1 pinpoint-sized telangiectasia on the chest of designed the study, collected data, and reviewed and revised the manuscript; Dr Zhao conceptualized and his mother and a vascular lesion on the forehead of his sister. Additionally, the designed the study, coordinated and supervised data patient’s father and great-uncle had a history of mild to moderate epistaxis. collection, and critically reviewed the manuscript for Mutation in GDF2 is a rare cause of HHT. Ours is the first report of important intellectual content; and all authors fi GDF2 approved the nal manuscript as submitted and homozygous -related HHT; in addition, this variant has not been agree to be accountable for all aspects of the work. fi reported previously. In our report, we also con rm variable expressivity, even DOI: https://doi.org/10.1542/peds.2019-1970 with the same pathogenic variant in GDF2-related HHT. Accepted for publication Jan 21, 2020 Address correspondence to Shunying Zhao, MD, Department of Respiratory Medicine, Beijing Children’s Hospital, National Center for Children’s Hereditary hemorrhagic telangiectasia to form abundant vascular networks Health and Capital Medical University, Beijing 100045, (HHT) is an autosomal dominant between the veins and arteries, People’s Republic of China. inherited disorder of blood vessel including telangiectasia, arteriovenous E-mail: [email protected] formation characterized by malformation (AVM) and arteriovenous PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, mucocutaneous and visceral vascular fistula.2,3 These malformations lead to 1098-4275). malformations resulting in direct variable clinical manifestations, Copyright © 2020 by the American Academy of communication between arterioles and depending on where they occur and to Pediatrics venules.1 This process is thought to what extent. One study revealed that FINANCIAL DISCLOSURE: The authors have indicated occur in a stepwise fashion, starting 30% of children who were initially they have no financial relationships relevant to this with dilation of postcapillary venules, negative for pulmonary arteriovenous article to disclose. followed by arteriolar dilation and then malformations (pAVMs) subsequently loss of the intervening capillary bed. developed within 5 years.4 Thus, To cite: Liu J, Yang J, Tang X, et al. Homozygous GDF2- Because of abnormal vascular children with HHT require continued Related Hereditary Hemorrhagic Telangiectasia in a Chinese Family. Pediatrics. 2020;146(2):e20191970 development, patients with HHT tend follow-up through adulthood.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 146, number 2, August 2020:e20191970 CASE REPORT 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 telangiectasia6–8 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 FIGURE 1 definitively if a child with a family The family tree with male in N, female in ○, epistaxis in blue, and telangiectasias in brown is shown. history of HHT has the condition, and P, proband. genetic testing is also helpful if children have $1 symptoms of HHT. vascular-anomaly syndrome have CASE PRESENTATION Because they may not yet meet 14,16 been reported. All of these cases A boy, aged 5 years and 2 months, criteria, when genetic test results are were heterozygous. The individuals presented with a 1-year history of positive, it will confirm the diagnosis presented with relatively infrequent decreased activity and cyanosis after regardless of family history or and mild nosebleeds, and small exercise (82%–85% of pulse oxygen symptoms. blanching vascular lesions (larger saturation [SpO ]). He was the than typical telangiectases) on the 2 product of a consanguineous In most cases, HHT is caused by upper body and trunk rather than marriage; his parents were second a mutation in 1 of 2 genes: endoglin limited to the hands, face, and mouth cousins (Fig 1). His family history (HHT 1) or activin receptor-like (as is typical of HHT), so GDF2-related revealed that his father had had a few kinase I/activin A receptor, type II- syndrome sometimes was reported as episodes of mild epistaxis when he like kinase 1 (ALK1/ACVRL1) (HHT “similar” to HHT.14 A single case 11 was a school-aged child, although he 2). A minor proportion of affected report identified a case of childhood- never required medical intervention. individuals have mutations in 2 onset pulmonary artery hypertension His mother and his sister (age 3) had additional loci that have not yet had harboring a homozygous GDF2 a gene identified on chromosome truncating mutation (p.Q263),17 and never experienced nosebleeds. His 12 5q31 (HHT 3) or chromosome 7q14 recent studies have independently paternal uncle had recurrent mild to 13 (HHT 4), in the growth identified heterozygous GDF2 moderate epistaxis into adulthood differentiation factor 2 (GDF2)/ mutations in pulmonary artery (Fig 1). Physical examinations (PEs) bone morphogenetic protein (BMP)9 hypertension cohorts.18 Additionally, revealed only 1 pinpoint-sized 14 gene (HHT 5) or in the SMAD family RAS p21 protein activator (RASA)1 telangiectasia on the right chest of his member 4 (SMAD4) gene (combined and ephrin receptor B4 (EPHB4) mother and no telangiectasias on him syndrome of juvenile polyposis and mutations cause capillary or his father (Fig 1). His sister had 3 HHT, also associated with malformation–AVM, which also a dull purple vascular lesion (3 2 15 aortopathy). There have been shows some overlap with HHT.16,19 mm) on her forehead at birth that reported differences between GDF2- persisted into childhood, unlike the related vascular-anomaly syndrome In this study, we report on a pediatric expected course for nevus simplex and HHT.14 To our knowledge, only 4 patient who presented with isolated (Fig 2A). His sister had no additional individuals with GDF2-related hypoxemia. cutaneous vascular lesions. His

Downloaded from www.aappublications.org/news by guest on September 30, 2021 2 LIU et al 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 3 106/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 FIGURE 2 performed and revealed radioactivity 3 – A, A vascular lesion (3 2 mm) on the left forehead of the sister of the proband. B D, A in the brain and bilateral kidney, 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 suggesting the existence of radioactivity in the bilateral kidney, suggesting the existence of a intrapulmonary shunt. intrapulmonary shunt due to pAVMs (Fig 2 E and F). Using trio whole- exome sequencing, we identified routine blood test revealed a red obvious shortness of breath at rest. a homozygous variant blood cell count of 5.36 3 1012/L and Blood count revealed a Hb level of [c.1060_1062delinsAG a hemoglobin (Hb) level of 15.5 g/dL, 10.5 to 14.6 g/dL and a platelet count (p.Tyr354ArgfsTer15)] in GDF2 in suggesting a mild polycythemia. The of 374 3 109/L. In laboratory our proband, which had been patient was initially suspected of investigations, we detected normal inherited from both of his having a hemoglobinopathy such as liver enzymes and renal function. heterozygous parents. The patient methemoglobinemia. Hb Screening for metabolic diseases, received treatment with intermittent electrophoresis revealed no contrast-enhanced (CE) lung low-flow supplemental oxygen and abnormalities. Sanger sequencing computed tomography (CT) (slice was lost to follow-up. results of CYB5A and CYB5R3, thickness 1.25 mm) with vascular associated with methemoglobinemia, three-dimensional reconstruction, We ultimately diagnosed homozygous were negative. noncontrast echocardiography, GDF2-related HHT in the patient and abdominal ultrasonography, and heterozygous GDF2-related HHT in At initial presentation to the abdominal CE-CT revealed no his parents. Transthoracic contrast respiratory medicine clinic, a PE abnormalities. Additionally, CE-CT did echocardiography was not performed revealed a body weight of 19.5 kg, not reveal aortic root dilation. during the initial hospitalization cyanosis of nail beds, and clubbed Noncontrast MRI of the brain was because the diagnosis of HHT was not fingers. His BMI was 16.1. He had no performed, which revealed punctate considered until the genetic testing

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 146, number 2, August 2020 3 resulted, mainly because of our detected by the otolaryngologist. parents do not currently have limited awareness of HHT at Noncontrast echocardiography was symptoms, and their SpO2 were 100% that time. normal with no evidence of in sitting, standing, and lying pulmonary hypertension. positions. None of the 4 family Three years later at the age of 8 years, Conventional PF revealed small members had any new skin findings he developed mild epistaxis (mainly airway impairment with a 52.6% of at recent follow-up. ∼ dripping and lasting for 1 minute) forced expiratory flow 75. Lung occurring every 2 to 5 months, diffusion capacity for carbon Vascular endothelial growth factor although he never required medical (VEGF) has been shown to be an monoxide (DLCO) revealed moderate 20 intervention. Transthoracic contrast reduction (52.5%, normal range is important biomarker in HHT. echocardiography at that time was 80%–120%). He started treatment Serum VEGF was elevated in HHT positive with Barzilai grade 3 (5 2 patients compared to control with sirolimus (0.8 mg/m once daily 20 beats, a large number of orally) 4 months ago, at the age of subjects. Importantly, it might be microbubbles), and angiogram a potential predictive biomarker for 9 years. SpO2 increased to 87% on 21 revealed diffuse pAVMs (distortion of therapeutic response in HHT. nasal cannula (fraction of inspire O2 of diffuse pulmonary small arteries and 90%–93%; flow of 2.0 L per minute), Therefore, serum VEGF levels were capillary beds). Abdominal his physical strength improved evaluated in this patient, in addition ultrasonography and abdominal CE- significantly, and he could run after to endoglin. Results of serum CT were normal. The following year endoglin and VEGF in the family 14 days on treatment. However, SpO2 members and control subjects are at the age of 9, SpO2 was 79% to 82% began to fall after 1 month on summarized in Table 1. (nasal cannula oxygen, fraction of treatment. When SpO further – fl 2 inspire O2 90% 93%; ow of 2.0 L decreased to 80%, sirolimus was per minute), and he was no longer discontinued after 3 months of DISCUSSION experiencing nosebleeds. He was treatment. more prone to fatigue, and he had The proband and his sister were difficulty walking to school (1 km). A Sanger sequencing revealed the same confirmed to have rare homozygous PE revealed abundant vascular homozygous variant in his now 7- GDF2-related HHT, and their parents networks in his ears but no discrete year-old sister. Her conventional PF were confirmed to have heterozygous cutaneous vascular malformations. was normal, but DLCO revealed GDF2-related HHT by genetic testing. No nasal telangiectasias were a mild reduction (61.5%). She and her The GDF2 p.Tyr354ArgfsTer15 is

TABLE 1 Results of Serum Endoglin and VEGF in the Family Members Patient Age, y Endoglin, ng/mL VEGF, pg/mL Proband 9 —— 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 7 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) 6 —— Before treatment — 23.5 67.9 14 d after start of treatment with sirolimus — 24.0 112.0 Control 6 (BP, male) 1 17.7 245.7 Control 7 (ILD, male) 1 12.4 7.6 Control 8 (SMPP-AO, male) 6 11.3 236.0 Control 9 (SMPP, female) 11 15.7 391.7 Control 10 (BP, male) 2 30.1 180.0 Control 11 (ILD, male) 9 12.7 220.9 Control 12 (SMPP, female) 12 21.6 416.6 Control 13 (SMPP, male) 5 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.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 4 LIU et al a likely pathogenic variant according be the potential mechanism of reduction, suggesting injury of to the American College of Medical atypical HHT and the cause of the pulmonary capillary endothelial cells. Genetics standards and guidelines,22 mild HHT phenotype in some family because the mutation is predicted to members. We predict that Our patient and his family members result in loss of function. heterozygous individuals have did not meet clinical criteria for HHT fi Pathogenicity is further supported by a milder phenotype than homozygous and were therefore dif cult to its absence in Exome Aggregation individuals because of the dosage diagnose with HHT. However, Consortium (ExAC), “1000G,” and effect (50% versus presumed 0% loss hypoxemia (clubbing, polycythemia) Genome Aggregation Database of function of GDF2). In examining the suggested possible pAVMs, which is (gnomAD). GDF2 binds with high family tree, we identified only 4 other highly associated with HHT. The affinity to ALK1 and endoglin, thereby affected relatives, which did not parents declined the recommended screening outlined by the activating downstream SMAD1/ reveal a rigorous cosegregation 1 SMAD5 via the transforming growth because the mother and the sister do international HHT guidelines for factor-b (TGF-b) signaling pathway, not have epistaxis or other visible themselves, their daughter, and their which may regulate signs of HHT, and it implies that low mothers because they believe that – angiogenesis.23 25 The amino acid penetration or variable expressivity they and their heterozygous family residues Ser24 and Arg78 of GDF2 are may occur. Given that only 3 family members are healthy, including their the shared conserved binding sites of members presented with mild or sister grandmothers at 80 years of all TGF-b ligands, and Lys64 is the moderate epistaxis (epistaxis severity age. They have had few nosebleeds core binding site of the GDF2-ALK1 score of 0–3), it also suggests that the (present in only 3 family members) complex,26 so in theory, the truncated gene dosage effect may play a role in and no classic skin lesions. The GDF2 protein chain resulting from our cases with atypical HHT, which location and relatively large size of ’ p.Tyr354ArgfsTer15 may not affect may be attributed to the specific the vascular lesion in the proband s the GDF2-mediated TGF-b signaling GDF2 mutation. sister are not typical for those pathway. GDF2 binds to endoglin described in classic HHT (caused by ACVRL1 mainly through amino acid 402-416 Both our patient and his sister are endoglin and ) but are of the protein chain,27 suggesting that homozygous for the GDF2 gene consistent with previous reports of GDF2- the truncation of GDF2 in this region variation inherited from their atypical lesions in related HHT. heterozygous parents. The parents will result in inactivation of the Some studies reveal that HHT can be GDF2 are second cousins, so we speculate endoglin- signaling pathway misdiagnosed as asthma or other b rather than the TGF- pathway. that the mutation was passed in diseases, because of the subclinical GDF2 Several cases of -related heterozygous form from one of their presentation (such as failure to thrive syndrome may have provided clues to great-grandparents, through their and/or mild cough) at the time of GDF2 the polypeptide chain required grandmothers and mothers. The investigation.7,28 In addition, many of GDF2 ALK1 to maintain the - complex proband had a homozygous mutation the symptoms of HHT are age-related. function that the pathogenic exhibiting more severe clinical Most patients report the appearance GDF2 mutations of mainly occurred in symptoms at an earlier age than of telangiectases during the third the other 2 core binding regions of previous family members. We predict decade.29 In HHT, AVMs typically GDF2 ALK1 the - complex, that is, that heterozygous individuals may occur in pulmonary, not bronchial, Pro85 and Arg68, demonstrated by have only mild or even no symptoms, 14 vasculature. However, in our present Wooderchak-Donahue et al. whereas the homozygous individual study, bronchoscopy revealed slightly Additionally, the missense mutation has more severe symptoms because increased small blood vessels and GDF2 at Arg333 mainly affects the synthesis of complete loss of function. submucosal spot (nonpinpoint) and maturation of the GDF2 protein, However, his homozygous sister 14 hemorrhages primarily localized to resulting in its decreased activity. In remains asymptomatic at the age of the wall of left main bronchus, our cases, the pathogenic mutations 7 years, which suggests variability in suggesting an increased pressure in GDF2 of revealed a dose effect. The penetrance and severity of phenotype the pulmonary and bronchial GDF2 protein shortened by mutation, despite shared genotype. His sister circulation, and suspicious for Tyr354ArgfsTer15, may not affect the might develop more symptoms with bronchial vascular malformation. To b activation of the TGF- signaling time, and we have not performed our knowledge, only 1 patient has GDF2 ALK1 pathway regulated by - , but a bubble echo to determine if she has been reported to have telangiectases the loss of endoglin-binding region, any intrapulmonary shunt that is not of the bronchial mucosa.30 that is, amino acid 402–416, would yet causing an issue with oxygen result in complete loss of endoglin- saturation. Although her conventional The prevalence of pAVMs is higher in GDF2 complex function, which might PF was normal, DLCO revealed mild endoglin-related HHT than in ALK1-

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 146, number 2, August 2020 5 related HHT.28 pAVMs may be concentration of serum VEGF among affected individuals, which asymptomatic; present as respiratory increased, so sirolimus was may be due in part to, but is not symptoms of hemoptysis, dyspnea, discontinued after 3 months of completely explained by, gene dosage. hypoxemia or digital clubbing; or treatment. One recent study revealed present with neurologic symptoms that combined correction of ACKNOWLEDGMENTS because of paradoxical emboli endothelial Smad1/5/8, mammalian including stroke, transient ischemic target of rapamycin (mTOR), and We thank Ke Xu, Xiaofang Quan, and attacks, or unusual infections, VEGF receptor 2 (VEGFR2) pathways other staff at Beijing Chigene including brain abscesses.7,28 In the opposes HHT pathogenesis36 and may Translational Medicine Research first hospitalization of our proband, explain our treatment failure of Center for their expert technical assistance. We thank Xiaoyan Zhang SpO2 was as low as 82% to 85%, sirolimus alone. Repurposing of suggesting a pAVM of such size that it sirolimus (mTOR inhibitor) in (Capital Medical University) for should have been detected on chest conjunction with a VEGF inhibitor performing the enzyme-linked CT. In the absence of visible large such as nintedanib might provide immunosorbent assay experiment pAVM, we speculated that there were therapeutic benefit in HHT patients.36 and Yixin Ren and Nannan Jiang multiple small or even diffuse pAVMs. As shown in Table 1, VEGF might not (Department of Pulmonary Function ’ Although brain MRI revealed no completely be associated with disease at Beijing Children s Hospital) for evidence of AVMs, it did reveal severity, and it may increase in performing lung function for the multiple punctate lesions consistent mycoplasma pneumoniae pneumonia children. We thank Dr Hui Xu and the with previous paradoxical emboli patients37 and other control nurses in our department and Xin through pAVMs. individuals, but it may be used to Zhang in the heart center at Beijing ’ dynamically assess treatment Children s Hospital for their HHT is a progressive vascular disease response. Serum endoglin was cooperation. We thank the patient with potential mortality. Although normal in the family, and it could help and his family for their kind there is no cure for HHT, there are to exclude HHT caused by endoglin cooperation. We also thank the treatments for the symptoms of HHT. defects. However, further functional reviewers for their substantial Targeted anti-angiogenic therapies studies should be conducted to revision of this article. have shown great promise including – confirm these mechanismal bevacizumab and pazopanib.31 33 hypotheses. Bevacizumab, an anti-VEGF antibody, ABBREVIATIONS is a rational therapeutic for HHT There are few published reports of because it may reduce excessive patients with GDF2 mutations to date ALK1: activin receptorlike kinase I angiogenesis, which can improve and none with our present AVM: arteriovenous malformation quality of life, decreasing nasal and/ mutation.9,11 In addition, the CE: contrast-enhanced or gastrointestinal bleeding.31,32 homozygous state has never been CT: computed tomography Unfortunately, bevacizumab is not reported, constituting an important DLCO: lung diffusion capacity for available at our hospital. Pazopanib new finding for researchers and carbon monoxide may reduce bleeding in HHT,33 but clinicians studying HHT. GDF2: growth differentiation has not yet become available in China. factor 2 Oral low-dose tacrolimus improved CONCLUSIONS Hb: hemoglobin ALK1-HHT-associated epistaxis in one HHT: hereditary hemorrhagic study.34 Recent studies have revealed HHT can be clinically diagnosed by telangiectasia that PI3K-Akt signaling is using the Curaçao criteria, but pAVM: pulmonary arteriovenous overactivated in several HHT models children often lack characteristic malformation and that its inhibition reduces the features. HHT should be considered PE: physical examination AVMs.35 Our proband ultimately in the differential diagnosis of PF: pulmonary function started treatment with sirolimus. His hypoxemia, even isolated hypoxemia. SpO2: pulse oxygen saturation symptoms improved, and the GDF2 mutations can be homozygous TGF-b: transforming growth fac- concentration of serum VEGF whereas other HHT-related genes tor-b decreased within 1 month. have not been reported in the VEGF: vascular endothelial growth Subsequently, however, his SpO2 homozygous state. GDF2-related HHT factor started to decrease, and the reveals variability in phenotype

Downloaded from www.aappublications.org/news by guest on September 30, 2021 6 LIU et al 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). POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/146/2/e20191970 References This article cites 37 articles, 8 of which you can access for free at: http://pediatrics.aappublications.org/content/146/2/e20191970#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Community Pediatrics http://www.aappublications.org/cgi/collection/community_pediatrics _sub Pulmonology http://www.aappublications.org/cgi/collection/pulmonology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 30, 2021 Homozygous GDF2-Related Hereditary Hemorrhagic Telangiectasia in a Chinese Family Jinrong Liu, Jigang Yang, Xiaolei Tang, Huimin Li, Yuelin Shen, Weiyue Gu and Shunying Zhao Pediatrics 2020;146; DOI: 10.1542/peds.2019-1970 originally published online July 15, 2020;

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