Peripheral pulmonary arterial stenoses - at/beyond hilar bifurcation

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  Chromosomal map of CHD genes and imbalances.

Non syndromic associated genes overview

JAG1 (2, 5.7%)

ELN (33, 94.3%)

Peripheral pulmonary arterial stenosis (PPS) is frequently seen in neonates due to narrowing of the pulmonary arteries at the level of the main pulmonary artery, at its bifurcation, or at the bifurcation of more distal branches. PPS may occur at a single level, but multiple sites of obstruction are more common. PPS may be associated with other congenital heart anomalies such as valvular PS, atrial septal defect, ventricular septal defect, patent ductus arteriosus, or tetralogy of Fallot.

If the level of obstruction is not further specified, the term pulmonary arterial stenosis is used.

External references for Peripheral pulmonary arterial stenoses - at/beyond hilar bifurcation

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Genes for phenotype 09.10.06:Peripheral pulmonary arterial stenoses - at/beyond hilar bifurcation

Non-syndromic

ELN

Support: confirmed: 2 or more independent reports > 1% incidence References: PMID:16944981 (single case report ) PMID:8475063 (basic research ) PMID:11175284 (population study with screening of similar CHD patients and normal controls ) PMID:10942104 (population study with screening of similar CHD patients and normal controls ) Inheritance: Isolated sporadic or autosomal dominant familial SVAS with central or peripheral pulmonary artery stenosis Incidence: Mutations in ELN were detected in 35 out of 100 patients with SVAS and normal karyotypes (Metcalfe K et al., 2000). Comments: Studies: (4) [ show ] [ hide ] Reference: PMID:21080980 Incidence: 2/8 patients Comments: Jakob A et al., 2011 report on a heterozygous ELN mutation in a large family with 8 affected members: 2 patients presented with isolated SVAS, 2 with aortic valve stenosis, 1 with peripheral pulmonary stenosis and 1 with pulmonary valve stenosis. The two remaining mutation carriers died at young age due to heart failure: one patient presented with AS/PS and coronary stenosis, and the other patient with SVAS, PPS, CoAo and coronary abnormalities. Reference: PMID:11175284 Incidence: 27/35 patients Comments: Metcalfe K et al., 2000 reported on ELN mutations in 35 out of 100 patients with supravalvar aortic stenosis (SVAS) and/or peripheral pulmonary stenosis (PPS). Personal or familial history of PPS was reported in 27 ELN mutation carriers. Reference: PMID:10942104 Incidence: 4/5 patients Comments: Urban Z et al., 2000 reported on heterozygous ELN mutations in 4 large families with SVAS and peripheral pulmonary stenosis. In addition, a patient with SVAS and PPS was found compound heterozygous for ELN mutations. The presence of unaffected carriers in these families suggests that ELN mutations are associated with reduced penetrance. Reference: PMID:16944981 Incidence: 1/1 patients Comments: Arrington CB et al., 2006 reported on an ELN mutation a large family with SVAS and supravalvar pulmonary stenosis (SVPS). Ten mutation carriers were diagnosed with SVAS, which was associated with SVPS in 7 individuals. Add another study.

JAG1

Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene) References: PMID:20437614 (population study with screening of similar CHD patients and normal controls ) Inheritance: Non-syndromic peripheral pulmonary valvar stenosis. Incidence: Rare Comments: Studies: (3) [ show ] [ hide ] Reference: PMID:12427653 Incidence: 60/154 patients Comments: McElhinney et al. studied the spectrum of cardiac anomalies associated with JAG1 positive Alagille syndrome. Mutations in the JAG1 gene were found in 154 out of 200 individuals with Alagille syndrome. Cardiac anomalies were present in 119 individuals carrying a JAG1 mutation. Eleven patients presented with valvar pulmonary stenosis (7%), 60 with branch pulmonary stenosis (39%), 20 with Tetralogy of Fallot (13%), 9 with left-sided anomalies (6%), and others CHD in 17 individuals (VSD in 4%, ASD in 5%,...) Reference: PMID:19948535 Incidence: 2/230 patients Comments: Rauch R et al., 2009 studied 230 patients with tetralogy of Fallot by karyotyping, comprehensive 22q11.2 deletion testing and sequencing of TBX1, NKX2.5 and JAG1, as well as molecular karyotyping in selected patients. Mutations in JAG1 were detected in 3 TOF patients with features of Alagille syndrome. Peripheral pulmonary stenosis was present in two of them. Reference: PMID:20437614 Incidence: 2/50 patients Comments: Bauer RC et al., 2010 performed mutation analysis in 144 cases of right-sided heart defects (94 with Tetralogy of Fallot and 50 with pulmonary valvar stenosis/atresia or peripheral pulmonary stenosis) for mutations in the JAG1 gene. Sequence changes were identified in three TOF and three PS/PPS/PA patients, that were not present in 100 controls. Functionally significant mutations were detected in 2% (2/94) of TOF patients and 4% (2/50) of PS/PPS/PA patients. With the exception of one case with ToF and posterior embryotoxon, no other features of Alagille syndrome were present in these cases. Add another study.

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Syndromic

ELN

Support: confirmed: 2 or more independent reports > 1% incidence References: PMID:16930010 (review ) PMID:9071842 (single case report ) PMID:15149554 (basic research ) PMID:14666267 (population study with screening of similar CHD patients and normal controls ) Syndromes: Williams-Beuren syndrome (OMIM:194050): autosomal dominant: supravalvular aortic stenosis (SVAS) (isolated or associated with pulmonary artery stenosis, mitral valve prolapse (MVP), bicuspid aortic valve (BAV), aortic coarctation (CoAo), valvular aortic stenosis (VAS), subaortic stenosis, or with multiple peripheral pulmonary arterial stenoses) or isolated pulmonary artery stenosis, elfin face, mental and statural deficiency, characteristic dental malformation, and infantile hypercalcemia Incidence: Allelic loss of ELN in 2 children with Williams and supravalvular aortic stenosis (SVAS) and peripheral pulmonary stenosis (PPS) (PMID:9071842); ELN microdeletion in 17/20 patients with Williams-Beuren syndrome: CHD in 16 patients: isolated (2/16) supravalvular aortic stenosis and supravalvular aortic stenosis associated (11/16) with pulmonary artery stenosis (4/11); mitral valve prolapse (3/11); bicuspid aortic valve (3/11); aortic coarctation (2/11), thickened pulmonary valve (2/11); pulmonary valvular stenosis (1/11); supravalvular pulmonary stenosis (1/11); valvular aortic stenosis (1/11); fixed subaortic stenosis (1/11); pulmonary artery stenosis (2/16) associated with pulmonary valvar stenosis (1/2) and with mitral valve prolapse (1/2); and isolated mitral valve prolapse (1/16) (PMID:14666267) Comments: Studies: (4) [ show ] [ hide ] Reference: PMID:21080980 Incidence: 2/8 patients Comments: Jakob A et al., 2011 report on a heterozygous ELN mutation in a large family with 8 affected members: 2 patients presented with isolated SVAS, 2 with aortic valve stenosis, 1 with peripheral pulmonary stenosis and 1 with pulmonary valve stenosis. The two remaining mutation carriers died at young age due to heart failure: one patient presented with AS/PS and coronary stenosis, and the other patient with SVAS, PPS, CoAo and coronary abnormalities. Reference: PMID:11175284 Incidence: 27/35 patients Comments: Metcalfe K et al., 2000 reported on ELN mutations in 35 out of 100 patients with supravalvar aortic stenosis (SVAS) and/or peripheral pulmonary stenosis (PPS). Personal or familial history of PPS was reported in 27 ELN mutation carriers. Reference: PMID:10942104 Incidence: 4/5 patients Comments: Urban Z et al., 2000 reported on heterozygous ELN mutations in 4 large families with SVAS and peripheral pulmonary stenosis. In addition, a patient with SVAS and PPS was found compound heterozygous for ELN mutations. The presence of unaffected carriers in these families suggests that ELN mutations are associated with reduced penetrance. Reference: PMID:16944981 Incidence: 1/1 patients Comments: Arrington CB et al., 2006 reported on an ELN mutation a large family with SVAS and supravalvar pulmonary stenosis (SVPS). Ten mutation carriers were diagnosed with SVAS, which was associated with SVPS in 7 individuals. Add another study.

JAG1

Support: confirmed: 2 or more independent reports > 1% incidence References: PMID:12427653 (population study with screening of similar CHD patients and normal controls ) Syndromes: Alagille Syndrome (OMIM:118450) is an autosomal dominant disorder characterized by neonatal jaundice, eye anomalies (posterior embryotoxon and retinal pigmentary changes), cardiac anomalies (pulmonic valvular stenosis, ToF, peripheral arterial stenosis), bone defects ('butterfly' vertebrae and decrease in interpediculate distance in the lumbar spine), neurological abnormalities (absent deep tendon reflexes and poor school performance) and facial dysmorphic features (broad forehead, pointed mandible and bulbous tip of the nose). Incidence: McElhinney et al. studied the spectrum of cardiac anomalies associated with JAG1 positive Alagille syndrome. Mutations in the JAG1 gene were found in 154 out of 200 individuals with Alagille syndrome. Cardiac anomalies were present in 119 individuals carrying a JAG1 mutation. Eleven patients presented with valvar pulmonary stenosis (7%), 60 with branch pulmonary stenosis (39%), 20 with Tetralogy of Fallot (13%), 9 with left-sided anomalies (6%), and others CHD in 17 individuals (VSD in 4%, ASD in 5%,...) Comments: Studies: (3) [ show ] [ hide ] Reference: PMID:12427653 Incidence: 60/154 patients Comments: McElhinney et al. studied the spectrum of cardiac anomalies associated with JAG1 positive Alagille syndrome. Mutations in the JAG1 gene were found in 154 out of 200 individuals with Alagille syndrome. Cardiac anomalies were present in 119 individuals carrying a JAG1 mutation. Eleven patients presented with valvar pulmonary stenosis (7%), 60 with branch pulmonary stenosis (39%), 20 with Tetralogy of Fallot (13%), 9 with left-sided anomalies (6%), and others CHD in 17 individuals (VSD in 4%, ASD in 5%,...) Reference: PMID:19948535 Incidence: 2/230 patients Comments: Rauch R et al., 2009 studied 230 patients with tetralogy of Fallot by karyotyping, comprehensive 22q11.2 deletion testing and sequencing of TBX1, NKX2.5 and JAG1, as well as molecular karyotyping in selected patients. Mutations in JAG1 were detected in 3 TOF patients with features of Alagille syndrome. Peripheral pulmonary stenosis was present in two of them. Reference: PMID:20437614 Incidence: 2/50 patients Comments: Bauer RC et al., 2010 performed mutation analysis in 144 cases of right-sided heart defects (94 with Tetralogy of Fallot and 50 with pulmonary valvar stenosis/atresia or peripheral pulmonary stenosis) for mutations in the JAG1 gene. Sequence changes were identified in three TOF and three PS/PPS/PA patients, that were not present in 100 controls. Functionally significant mutations were detected in 2% (2/94) of TOF patients and 4% (2/50) of PS/PPS/PA patients. With the exception of one case with ToF and posterior embryotoxon, no other features of Alagille syndrome were present in these cases. Add another study.

MGP

Support: confirmed: 2 or more independent reports > 1% incidence References: PMID:9916809 (population study with screening of similar CHD patients and normal controls ) PMID:15810001 (single case report ) Syndromes: Keutel syndrome (OMIM:245150): rare recessive syndrome characterized by diffuse cartilaginous calcification, nasal hypoplasia, brachytelephalangy, peripheral pulmonary stenosis Incidence: Hur et al. review the literature on Keutel syndrome: peripheral pulmonary stenosis occurs in 14/20 patients (70%) with Keutel syndrome in 8 different families. Comments: Studies: (2) [ show ] [ hide ] Reference: PMID:15810001 Incidence: 2/3 patients Comments: Hur et al. report on a consanguineous family with Keutel syndrome. All 3 affected family members carry a homozygous mutation of the MGP gene and two of them presented with peripheral pulmonary stenosis. Reference: PMID:9916809 Incidence: 3/3 patients Comments: Munroe et al. performed mutation analysis of MGP in 3 families with Keutel syndrome. All three KS families analysed in this study have mutations in MGP that predict absent or non-functional MGP. Peripheral pulmonary stenosis was present in all reported families. Add another study.

NOTCH2

Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene) References: PMID:16773578 (population study with screening of similar CHD patients and normal controls ) Syndromes: Alagille Syndrome (OMIM:118450): neonatal jaundice; eye (posterior embryotoxon and retinal pigmentary changes); heart (pulmonic valvular stenosis, ToF, peripheral arterial stenosis); bones ('butterfly' vertebrae and decrease in interpediculate distance in the lumbar spine); nervous system (absent deep tendon reflexes and poor school performance); facies (broad forehead, pointed mandible and bulbous tip of the nose); fingers (varying degrees of foreshortening) Incidence: Comments: Studies: (1) [ show ] [ hide ] Reference: PMID:16773578 Incidence: 2/11 patients Comments: McDaniell et al. screened 11 JAG1 mutation-negative probands with Alagille syndrome for alterations in the gene for the Notch2 receptor (NOTCH2)and found NOTCH2 mutations segregating in two families. The first proband presented with peripheral pulmonic stenosis and a small atrial septal defect. The mutation was inherited from an affected mother who presented with valvular and peripheral pulmonic stenosis. The second proband presented with tetralogy of Fallot. Add another study.

GPC3

Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene) References: PMID:10232747 (population study with screening of similar CHD patients and normal controls ) Syndromes: Simpson-Golabi-Behmel syndrome (OMIM:312870) is an X-linked condition characterized by pre- and postnatal overgrowth, coarse facies and congenital heart defects (septal defects). Incidence: rare Comments: Studies: (1) [ show ] [ hide ] Reference: PMID:10232747 Incidence: 2/26 patients Comments: Lin et al., 1999 reviewed 101 patients with a clinical diagnosis of Simpson-Golabi-Behmel syndrome. A GPC3 mutation was detected in 26 SGBS patients. Cardiac anomalies were present in 12 out of 26 GPC3 positive patients. Two cases presented with pulmonary arterial stenosis. The pulmonary arterial stenosis was associated with a ventricular septal defect and patent ductus arteriosus in one case. Add another study.

PTPN11

Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene) References: PMID:17515436 (population study with screening of similar CHD patients and normal controls ) PMID:15470362 (single case report ) Syndromes: Noonan Syndrome 1 (NS1) (OMIM:163950): autosomal dominant condition characterized by short stature, distinctive facial appearance (triangular face with ptosis, blue-green irides and low posterior hairline or webbed neck), congenital heart defects (pulmonic stenosis, septal defects, and hypertrophic cardiomyopathy) and Woolly-like consistency of hair. Incidence: Sznayer et al. reports an incidence of 15% (16 out of 104) of peripheral pulmonary arterial stenosis in Noonan patients that carry a PTPN11 mutation. Comments: Studies: (2) [ show ] [ hide ] Reference: PMID:15470362 Incidence: 1/1 patients Comments: Sarkozy et al. reports on a patient with an overlapping phenotype of Noonan and LEOPARD syndrome, carrying a PTPN11 mutation. This patient presented with mild PVS, asymmetric septal hypertrophy, pulmonary artery branch stenosis and myxoid mitral valve. Reference: PMID:17515436 Incidence: 16/104 patients Comments: Sznayer et al. describes the cardiac phenotype of 104 patients with Noonan syndrome, which carry a mutation in the PTPN11 gene. Heart defects were present in 85%. The most prevalent CHDs were pulmonary valve stenosis (N=62 (60%)), atrial septal defect ostium secundum type (N=26(25%)), and stenosis of the peripheral pulmonary arteries (N=16 (15%)). Other CHDs: VSD (N=7); AVSD (N=2); hypertrophic cardiomyopathy (N=12); aortic stenosis (N=2) and CoAo (N=1). Add another study.

SLC2A10

Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene) References: PMID:16550171 (basic research ) PMID:17163528 (single case report ) Syndromes: Arterial tortuosity syndrome (ATS) (OMIM:208050) is a rare autosomal recessive disorder characterized by tortuosity and elongation of all major arteries including the aorta, multiple peripheral pulmonary arterial stenoses, soft skin, joint laxity and severe keratoconus. Incidence: Comments: Studies: (2) [ show ] [ hide ] Reference: PMID:16550171 Incidence: 6/6 patients Comments: Coucke et al. performed mutation analysis of the SLC2A10 gene in 6 families with arterial tortuosity syndrome. Reference: PMID:17163528 Incidence: 1/1 patients Comments: Drera et al. report on a case with arterial tortuosity syndrome with stenosis of the left pulmonary artery and tortuosity of carotid, vertebral, and intracerebral arteries. Add another study.

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Regions for phenotype 09.10.06:Peripheral pulmonary arterial stenoses - at/beyond hilar bifurcation

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Translocations 09.10.06:Peripheral pulmonary arterial stenoses - at/beyond hilar bifurcation

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Patients reports for 09.10.06:Peripheral pulmonary arterial stenoses - at/beyond hilar bifurcation

• case 92 Clinical data Phenotype

• case 101 Clinical data Phenotype

• case 1343 Clinical data Phenotype

Automated text-mining genes found for 09.10.06:Peripheral pulmonary arterial stenoses - at/beyond hilar bifurcation

AGeneApart Method

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This page contributors

• Jeroen Breckpot - CME Leuven (Belgium) (association, study)